CA3212074A1

CA3212074A1 - Antibacterial compounds

Info

Publication number: CA3212074A1
Application number: CA3212074A
Authority: CA
Inventors: Jerome Emile Georges Guillemont; Magali Madeleine Simone Motte; Dirk Antonie LAMPRECHT; Jose Manuel Bartolome-Nebreda
Original assignee: Janssen Sciences Ireland ULC
Current assignee: Janssen Sciences Ireland ULC
Priority date: 2021-03-17
Filing date: 2022-03-16
Publication date: 2022-09-22
Also published as: US20240182495A1; WO2022194906A1; KR20230157445A; MX2023010941A; JP2024509998A; CN117440958A; EP4308579A1; BR112023018654A2; AU2022236404A1

Abstract

The present invention relates to the compounds (I) wherein the integers are as defined in the description, and where the compounds may be useful as medicaments, for instance for use in the treatment of tuberculosis.

Description

ANTIBACTERIAL COMPOUNDS
The present invention relates to novel compounds. The invention also relates to such compounds for use as a pharmaceutical and further for the use in the treatment of bacterial diseases, including diseases caused by pathogenic mycobacteria such as Mycobacterium tuberculosis. Such compounds may work by interfering with ATP
synthase in M. tuberculosis, with the inhibition of cytochrome bci activity as the primary mode of action. Hence, primarily, such compounds are antitubercular agents.
BACKGROUND OF THE INVENTION
Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), a serious and potentially fatal infection with a world-wide distribution. Estimates from the World Health Organization indicate that more than 8 million people contract TB each year, and 2 million people die from tuberculosis yearly. In the last decade, TB
cases have grown 20% worldwide with the highest burden in the most impoverished communities.
If these trends continue, TB incidence will increase by 41% in the next twenty years.
Fifty years since the introduction of an effective chemotherapy, TB remains after AIDS, the leading infectious cause of adult mortality in the world.
Complicating the TB
epidemic is the rising tide of multi-drug-resistant strains, and the deadly symbiosis with HIV. People who are HIV-positive and infected with TB are 30 times more likely to develop active TB than people who are HIV-negative and TB is responsible for the death of one out of every three people with HIV/AIDS worldwide.
Existing approaches to treatment of tuberculosis all involve the combination of multiple agents. For example, the regimen recommended by the U.S. Public Health Service is a combination of isoniazid, rifampicin and pyrazinamide for two months, followed by isoniazid and rifampicin alone for a further four months. These drugs are continued for a further seven months in patients infected with HIV. For patients infected with multi-drug resistant strains of M. tuberculosis, agents such as ethambutol, streptomycin, kanamycin, amikacin, capreomycin, ethionamide, cycloserine, ciprofoxacin and ofloxacin are added to the combination therapies. There exists no single agent that is effective in the clinical treatment of tuberculosis, nor any combination of agents that offers the possibility of therapy of less than six months' duration.
There is a high medical need for new drugs that improve current treatment by enabling regimens that facilitate patient and provider compliance. Shorter regimens and those

-2-that require less supervision are the best way to achieve this. Most of the benefit from treatment comes in the first 2 months, during the intensive, or bactericidal, phase when four drugs are given together; the bacterial burden is greatly reduced, and patients become noninfectious. The 4- to 6-month continuation, or sterilizing, phase is required to eliminate persisting bacilli and to minimize the risk of relapse. A potent sterilizing drug that shortens treatment to 2 months or less would be extremely beneficial. Drugs that facilitate compliance by requiring less intensive supervision also are needed.
Obviously, a compound that reduces both the total length of treatment and the frequency of drug administration would provide the greatest benefit.
Complicating the TB epidemic is the increasing incidence of multi-drug-resistant strains or MDR-TB. Up to four percent of all cases worldwide are considered MDR-TB
- those resistant to the most effective drugs of the four-drug standard, isoniazid and rifampin. MDR-TB is lethal when untreated and cannot be adequately treated through the standard therapy, so treatment requires up to 2 years of "second-line"
drugs. These drugs are often toxic, expensive and marginally effective. In the absence of an effective therapy, infectious MDR-TB patients continue to spread the disease, producing new infections with MDR-TB strains. There is a high medical need for a new drug with a new mechanism of action, which is likely to demonstrate activity against drug resistant, in particular MDR strains.
The term "drug resistant" as used hereinbefore or hereinafter is a term well understood by the person skilled in microbiology. A drug resistant Mycobacterium is a Mycobacterium which is no longer susceptible to at least one previously effective drug;
which has developed the ability to withstand antibiotic attack by at least one previously effective drug. A drug resistant strain may relay that ability to withstand to its progeny.
Said resistance may be due to random genetic mutations in the bacterial cell that alters its sensitivity to a single drug or to different drugs.
MDR tuberculosis is a specific form of drug resistant tuberculosis due to a bacterium resistant to at least isoniazid and rifampicin (with or without resistance to other drugs), which are at present the two most powerful anti-TB drugs. Thus, whenever used herembefore or hereinafter "drug resistant" includes multi drug resistant.
Another factor in the control of the TB epidemic is the problem of latent TB.
In spite of decades of tuberculosis (TB) control programs, about 2 billion people are infected by M. tuberculosis, though asymptomatically. About 10% of these individuals are at risk of developing active TB during their lifespan. The global epidemic of TB is fuelled by

-3-infection of HIV patients with TB and rise of multi-drug resistant TB strains (MDR-TB). The reactivation of latent TB is a high risk factor for disease development and accounts for 32% deaths in HIV infected individuals. To control TB
epidemic, the need is to discover new drugs that can kill dormant or latent bacilli. The dormant TB
can get reactivated to cause disease by several factors like suppression of host immunity by use of immunosuppressive agents like antibodies against tumor necrosis factor cc or interferon-y. In case of HIV positive patients the only prophylactic treatment available for latent TB is two- three months regimens of rifampicin, pyrazinamide. The efficacy of the treatment regime is still not clear and furthermore the length of the treatments is an important constrain in resource-limited environments.
Hence there is a drastic need to identify new drugs, which can act as chemoprophylatic agents for individuals harboring latent TB bacilli.
The tubercle bacilli enter healthy individuals by inhalation; they are phagocytosed by the alveolar macrophages of the lungs. This leads to potent immune response and formation of granulomas, which consist of macrophages infected with M.
tuberculosis surrounded by T cells. After a period of 6-8 weeks the host immune response cause death of infected cells by necrosis and accumulation of caseous material with certain extracellular bacilli, surrounded by macrophages, epitheloid cells and layers of lymphoid tissue at the periphery. In case of healthy individuals, most of the mycobacteria are killed in these environments but a small proportion of bacilli still survive and are thought to exist in a non-replicating, hypometabolic state and are tolerant to killing by anti-TB drugs like isoniazid. These bacilli can remain in the altered physiological environments even for individual's lifetime without showing any clinical symptoms of disease. However, in 10% of the cases these latent bacilli may reactivate to cause disease. One of the hypothesis about development of these persistent bacteria is patho-physiological environment in human lesions namely, reduced oxygen tension, nutrient limitation, and acidic pH. These factors have been postulated to render these bacteria phenotypically tolerant to major anti-mycobacterial drugs.
In addition to the management of the TB epidemic, there is the emerging problem of resistance to first-line antibiotic agents. Some important examples include penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus, multi-resistant salmonellae.
The consequences of resistance to antibiotic agents are severe. Infections caused by resistant microbes fail to respond to treatment, resulting in prolonged illness and greater

-4-risk of death. Treatment failures also lead to longer periods of infectivity, which increase the numbers of infected people moving in the community and thus exposing the general population to the risk of contracting a resistant strain infection.
Hospitals are a critical component of the antimicrobial resistance problem worldwide.
The combination of highly susceptible patients, intensive and prolonged antimicrobial use, and cross-infection has resulted in infections with highly resistant bacterial pathogens.
Self-medication with antimicrobials is another major factor contributing to resistance.
Self-medicated antimicrobials may be unnecessary, are often inadequately dosed, or may not contain adequate amounts of active drug.
Patient compliance with recommended treatment is another major problem.
Patients forget to take medication, interrupt their treatment when they begin to feel better, or may be unable to afford a full course, thereby creating an ideal environment for microbes to adapt rather than be killed.
Because of the emerging resistance to multiple antibiotics, physicians arc confronted with infections for which there is no effective therapy. The morbidity, mortality, and financial costs of such infections impose an increasing burden for health care systems worldwide.
Therefore, there is a high need for new compounds to treat bacterial infections, especially mycobacterial infections including drug resistant and latent mycobacterial infections, and also other bacterial infections especially those caused by resistant bacterial strains.
Anti-infective compounds for treating tuberculosis have been disclosed in e.g.

international patent application WO 2011/113606. Such a document is concerned with compounds that would prevent 111 tuberculosis multiplication inside the host macrophage and relates to compounds with a bicyclic core, imidazopyridines, which are linked (e.g. via an amido moiety) to e.g. an optionally substituted benzyl group.
International patent application WO 2014/015167 also discloses compounds that are disclosed as being of potential use in the treatment of tuberculosis. Such compounds disclosed herein have a bicycle (a 5,5-fused bicycle) as an essential element, which is substituted by a linker group (e.g. an amido group), which itself may be attached to

-5-another bicycle or aromatic group. Such compounds in this document do not contain a series of more than three rings.
Journal article Nature Medicine, 19, 1157-1160 (2013) by Pethe et al "Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis"
identifies a specific compound that was tested against M tuberculosis. This compound Q203 is depicted below.
F\s/F___F

QQ
CI
This clinical candidates is also discussed in journal article, I Medicinal Chemistry, 2014, 57 (12), pp 5293-5305. It is stated to have activity against MDR
tuberculosis, and have activity against the strain M. tuberculosis H37Rv at a MIC50 of 0.28 nM
inside macrophages. Positive control data (using known anti-TB compounds bedaquiline, isoniazid and moxifloxacin) are also reported. This document also suggests a mode of action, based on studies with mutants. It postulates that it acts by interfering with ATP synthase in M. tuberculosis, and that the inhibition of cytochrome bci activity is the primary mode of action. Cytochrome bci is an essential component of the electron transport chain required for ATP synthesis. It appeared that Q203 was highly active against both replicating and non-replicating bacteria.
International patent application WO 2015/014993 also discloses compounds as having activity against M tuberculosis, as do international patent applications WO
2014/4015167, WO 2017/001660, WO 2017/001661, WO 2017/216281 and WO
2017/216283. International patent applications WO 2013/033070 and WO
2013/033167 disclose various compounds as kinase modulators.
The purpose of the present invention is to provide compounds for use in the treatment of bacterial diseases, particularly those diseases caused by pathogenic bacteria such as Mycobacterium tuberculosis (including the latent disease and including drug resistant

6 M tuberculosis strains). Such compounds may also be novel and may act by interfering with ATP synthase in M. tuberculosis, with the inhibition of cytochrome bci activity being considered the primary mode of action.
SUMMARY OF THE INVENTION
There is now provided a compound of formula (I) X4¨NrTh R2 (I) wherein A is a 5- or 6-membered ring, which may be aromatic or non-aromatic, and optionally containing 1 or 2 heteroatoms selected from nitrogen and sulfur;
B is a 5-membered heteroaryl group in which at least one of XI, X2 and X3 represents a heteroatom selected from nitrogen sulfur and oxygen;
Xl represents =N-, -S-, -0- or =C(R9a)-;
X2 represents =N-, -S-, -0- or =C(R9b)-;
X3 represents =N-, -S-, -0- or =C(R9 )-;
X4 represents =N- or X5 represents =N- or =C(R9e)-;
R' represents one or more (e.g. one, two or three) optional substituents independently selected from selected from halo (e.g. Cl, F), -R4a, -0-R4b, -C(=0)-R4'.
-C(=0)-N(R5)(R6), -CN and -N(R5a)R5b; or any two re groups may be taken together (when attached to adjacent atoms of the A ring) to form a 5- or 6-membered ring optionally containing one or two heteroatoms, and which ring is optionally substituted by one or two C1-3 alkyl substituents;
R2 is -C1-4 alkyl optionally substituted by one or more substituents selected from halo and -0C1_3 alkyl;
R3 is H. -lea, -C(=0)-leb, -S02-R8 or Het';

-7-R4a. and 4b lc independently represent hydrogen or -C1_4 alkyl (which, as mentioned herein) may be linear, branched or cyclic alkyl) optionally substituted by one or more substituents selected from halo (e.g. F), -0-CH3 and phenyl;
R4c is _c1_3 alkyl;
R5 and R6 are independently selected from H and -C1_3 alkyl;
R5a and R5b independently represent H, C1_6 alkyl or R5a and R5b are linked together to form a 3- to 6-membered ring;
R7 a represents -C1-4 alkyl, optionally substituted by one or more substituents selected from halo, -0C1-3 alkyl and Hee;
R7b is hydrogen or -C1_3 alkyl (optionally substituted by one or more fluoro atoms);
-128 is Hee, -N(R5c)R5d or -C1_4 alkyl optionally substituted by one or more substituents selected from halo (e.g. F) and -0-CH3;
lec and R5d independently represent H, C1-6 alkyl or R5c and R5d are linked together to form a 3- to 6-membered ring;
R9a, R9b, R9c, R9d and R9e independently represent H, halo, C1-4 alkyl (itself optionally substituted by one or more, e.g. one, substituent(s) selected from fluoro, -CN, -Rwa, _N(Rioc)Riod and/or _c(o)N(Rioe)Rior ) or -0-C1-4 alkyl (itself optionally substituted by one or more, e.g. one, substituent(s) selected from fluoro, -Rwg, -OR' and/or -N(Rwi)Rwl);
R10a, R101), R10c, Rlod, R10e, R10g, R1011, Rim and R' independently represent hydrogen or C1_3 alkyl (optionally substituted by one or more fluoro atoms);
Het', Het2 and Het3 independently represent a 5- or 6-membered aromatic ring containing one or two heteroatoms, preferably selected from nitrogen and sulfur, optionally substituted by one or more substitutents selected from halo and C1_3 alkyl (itself optionally substituted by one or more fluoro atoms), or a pharmaceutically-acceptable salt thereof, which compounds may be referred to herein as -compounds of the invention".
Pharmaceutically-acceptable salts include acid addition salts and base addition salts.
Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is

-8-insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
The pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms that the compounds of formula (I) are able to form. These pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.
butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
For the purposes of this invention solvates, prodrugs, N-oxides and stereoisomers of compounds of the invention arc also included within the scope of the invention.
The term "prodrug" of a relevant compound of the invention includes any compound that, following oral or parenteral administration, is metabolised in vivo to form that compound in an experimentally-detectable amount, and within a predetermined time (e.g. within a dosing interval of between 6 and 24 hours (i.e. once to four times daily)).
For the avoidance of doubt, the term "parenteral" administration includes all forms of administration other than oral administration.
Prodrugs of compounds of the invention may be prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, in vivo when such prodrug is administered to a mammalian subject. The modifications typically are achieved by synthesising the parent compound with a prodrug substituent.
Prodrugs include compounds of the invention wherein a hydroxyl, amino, sulthydryl, carboxy or carbonyl group in a compound of the invention is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxy or carbonyl group, respectively.
Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, esters groups of carboxyl functional groups, N-acyl derivatives and

-9-N-Mannich bases. General information on prodrugs may be found e.g. in Bundegaard, H. "Design of Prodrugs- p. 1-92, Elesevier, New York-Oxford (1985).
Compounds of the invention may contain double bonds and may thus exist as E
(entgegen) and Z (zusammen) geometric isomers about each individual double bond.
Positional isomers may also be embraced by the compounds of the invention. All such isomers (e.g. if a compound of the invention incorporates a double bond or a fused ring, the cis- and trans- forms, are embraced) and mixtures thereof are included within the scope of the invention (e.g. single positional isomers and mixtures of positional isomers may be included within the scope of the invention).
Compounds of the invention may also exhibit tautomerism. All tautomeric forms (or tautomers) and mixtures thereof are included within the scope of the invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerisations. Valence tautomers include interconversions by reorganisation of some of the bonding electrons.
Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or di astereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a 'chiral pool' method), by reaction of the appropriate starting material with a 'chiral auxiliary' which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by separation of the di astereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person.
All stereoisomers (including but not limited to diastereoisomers, enantiomers and atropisomers) and mixtures thereof (e.g. racemic mixtures) are included within the scope of the invention.

-10-In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined.
The compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
The present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2H, 3H, 13c, 14c , 13N, 150, 170, 180, 32F, 33F, 35s, 18F, 36c1, 1231, and 1251. Certain isotopically-labeled compounds of the present invention (e.g., those labeled with 3H
and 14C) are useful in compound and for substrate tissue distribution assays.
Tritiated (3H) and carbon-14 (14C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H
may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron emitting isotopes such as 150, 13N, and 18F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the description/Examples hereinbelow, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
Unless otherwise specified, Ci_q alkyl groups (where q is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two or three, as appropriate) of carbon atoms, be branched-chain, and/or cyclic (so forming a C3,1-cycloalk-y1 group). Such cycloalkyl groups may be monocyclic or bicyclic and may further be bridged. Further, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic.

-11-Such alkyl groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated (forming, for example, a C2,1 alkenyl or a C2_,,L alkynyl group). In a similar way, Ci_q alkylene groups represent Ci_q alkyl linker groups, i.e. -CF11- (CI alkylene or methylene), -CHICHI-, etc according to the number -q" of carbon atoms.
C3-q cycloalkyl groups (where q is the upper limit of the range) that may be specifically mentioned may be monocyclic or bicyclic alkyl groups, which cycloalkyl groups may further be bridged (so forming, for example, fused ring systems such as three fused cycloalkyl groups). Such cycloalkyl groups may be saturated or unsaturated containing one or more double bonds (forming for example a cycloalkenyl group).
Substituents may be attached at any point on the cycloalkyl group. Further, where there is a sufficient number (i.e. a minimum of four) such cycloalkyl groups may also be part cyclic.
The term "halo", when used herein, preferably includes fluoro, chloro, bromo and iodo.
Heterocyclic groups when referred to herein may include aromatic or non-aromatic heterocyclic groups, and hence encompass heterocycloalkyl and hetereoaryl.
Equally, "aromatic or non-aromatic 5- or 6-membered rings" may be heterocyclic groups (as well as carbocyclic groups) that have 5- or 6-members in the ring.
Heterocycloalkyl groups that may be mentioned include non-aromatic monocyclic and bicyclic heterocycloalkyl groups in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom), and in which the total number of atoms in the ring system is between 3 and 20 (e.g. between three and ten, e.g between 3 and 8, such as 5- to 8-). Such heterocycloalkyl groups may also be bridged.
Further, such heterocycloalkyl groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C2-q heterocycloalkenyl (where q is the upper limit of the range) group. C2_qheterocycloalkyl groups that may be mentioned include 7-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, azabicyclo[3.2.1]-octanyl, 8-azabicyclo-[3.2.1]octanyl, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrroly1), dioxolanyl (including 1,3-dioxolanyl), dioxanyl (including 1,3-dioxanyl and 1,4-dioxanyl), dithianyl (including 1,4-dithianyl), dithiolanyl (including 1,3-dithiolanyl), imidazolidinyl, imidazolinyl, morpholinyl, 7-oxabicyclo12.2.1Iheptanyl, 6-oxabicyclo-[3.2.1]octanyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, non-aromatic pyranyl,

-12-pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3-sulfolenyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridyl (such as 1,2,3,4-tetrahydropyridyl and 1,2,3,6-tetrahydropyridy1), thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including 1,3,5-trithianyl), tropanyl and the like.
Substituents on heterocycloalkyl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of heterocycloalkyl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system.
Heterocycloalkyl groups may also be in the N- or S- oxidised form. Heterocycloalkyl mentioned herein may be stated to be specifically monocyclic or bicyclic.
Aromatic groups may be aryl or heteroaryl. Aryl groups that may be mentioned include C6_20, such as C6_12 (e.g. C6_10) aryl groups. Such groups may be monocyclic, bicyclic or tricyclic and have between 6 and 12 (e.g. 6 and 10) ring carbon atoms, in which at least one ring is aromatic. C6-10 aryl groups include phenyl, naphthyl and the like, such as 1,2,3,4-tetrahydronaphthyl. The point of attachment of aryl groups may be via any atom of the ring system. For example, when the aryl group is polycyclic the point of attachment may be via atom including an atom of a non-aromatic ring.
However, when aryl groups are polycyclic (e.g. bicyclic or tricyclic), they are preferably linked to the rest of the molecule via an aromatic ring. Most preferred aryl groups that may be mentioned herein are "phenyl".
Unless otherwise specified, the term -heteroaryl" when used herein refers to an aromatic group containing one or more heteroatom(s) (e.g. one to four heteroatoms) preferably selected from N, 0 and S. Heteroaryl groups include those which have between 5 and 20 members (e.g. between 5 and 10) and may be monocyclic, bicyclic or tricyclic, provided that at least one of the rings is aromatic (so forming, for example, a mono-, bi-, or tricyclic heteroaromatic group). When the heteroaryl group is polycyclic the point of attachment may be via any atom including an atom of a non-aromatic ring.
However, when heteroaryl groups are polycyclic (e.g. bicyclic or tricyclic), they are preferably linked to the rest of the molecule via an aromatic ring. Heteroaryl groups that may be mentioned include 3,4-dihydro-111-isoquinolinyl, 1,3-dihydroisoindolyl, 1,3-dihydroisoindoly1 (e.g. 3,4-dihydro-1H-isoquinolin-2-yl, 1,3-dihydroisoindo1-2-yl, 1,3-dihydroisoindo1-2-y1; i.e. heteroaryl groups that are linked via a non-aromatic ring), or, preferably, acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzo-dioxoly1 (including 1,3-benzodioxoly1), benzofuranyl, benzofurazanyl, benzothiadiazolyl (including 2,1,3-benzothiadiazoly1), benzothiazolyl, benzoxadiazolyl

-13-(including 2,1,3-benzoxadiazoly1), benzoxazinyl (including 3,4-dihydro-2H-1,4-benzoxazinyl), benzoxazolyl, benzomorpholinyl, benzoselenadiazolyl (including 2,1,3-benzoselenadiazoly1), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl, imidazo11,2-alpyridyl, indazolyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiaziolyl, isothiochromanyl, isoxazolyl, naphthyridinyl (including 1,6-naphthyridinyl or, preferably, 1,5-naphthyridinyl and 1,8-naphthyridinyl), oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazoly1 and 1,3,4-oxadiazoly1), oxazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl (including 1,2,3,4-tetrahydroisoquinolinyl and 5,6,7,8-tetra-hydroisoquinolinyl), tetrahydroquinolinyl (including 1,2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl), tetrazolyl, thiadiazolyl (including 1,2,3-thiadiazolyl, 1,2,4-thiadiazoly1 and 1,3,4-thiadiazoly1), thiazolyl, thiochromanyl, thiophenetyl, thienyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazoly1 and 1,3,4-triazoly1) and the like. Substituents on heteroaryl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of heteroaryl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heteroaryl groups may also be in the N- or S- oxidised form. Heteroaryl groups mentioned herein may be stated to be specifically monocyclic or bicyclic. When heteroaryl groups are polycyclic in which there is a non-aromatic ring present, then that non-aromatic ring may be substituted by one or more =0 group. Most preferred heteroaryl groups that may be mentioned herein are 5-or 6-membered aromatic groups containing 1, 2 or 3 heteroatoms (e.g. preferably selected from nitrogen, oxygen and sulfur).
It may be specifically stated that the heteroaryl group is monocyclic or bicyclic. In the case where it is specified that the heteroaryl is bicyclic, then it may consist of a five-, six- or seven-membered monocyclic ring (e.g. a monocyclic heteroaryl ring) fused with another five-, six- or seven-membered ring (e.g. a monocyclic aryl or heteroaryl ring).
Heteroatoms that may be mentioned include phosphorus, silicon, boron and, preferably, oxygen, nitrogen and sulfur.
When "aromatic" groups are referred to herein, they may be aryl or heteroaryl.
When "aromatic linker groups- are referred to herein, they may be aryl or heteroaryl, as defined herein, are preferably monocyclic (but may be polycyclic) and attached to the

-14-remainder of the molecule via any possible atoms of that linker group.
However, when, specifically carbocylic aromatic linker groups are referred to, then such aromatic groups may not contain a heteroatom, i.e. they may be aryl (but not heteroaryl).
For the avoidance of doubt, where it is stated herein that a group may be substituted by one or more substituents (e.g. selected from C1_6 alkyl), then those substituents (e.g.
alkyl groups) are independent of one another. That is, such groups may be substituted with the same substituent (e.g. same alkyl substituent) or different (e.g.
alkyl) substituents.
All individual features (e.g. preferred features) mentioned herein may be taken in isolation or in combination with any other feature (including preferred feature) mentioned herein (hence, preferred features may be taken in conjunction with other preferred features, or independently of them).
The skilled person will appreciate that compounds of the invention that are the subject of this invention include those that are stable. That is, compounds of the invention include those that are sufficiently robust to survive isolation from e.g. a reaction mixture to a useful degree of purity.
The invention may be described in several embodiments of the invention as follows:
R2 is -C1-4 alkyl optionally substituted by one or more substituents selected from halo;
R3 is H, -R7a, -C(=0)-R7b or -S02-R8;
R4a and R4b independently represent hydrogen or -C1-4 alkyl optionally substituted by one or more substituents selected from halo (e.g. F) and -0-CH3;
R7a represents -C1-4 alkyl, optionally substituted by one or more substituents selected from halo, -0C1-3 alkyl and -CN;
R7b represents -C1-3 alkyl (optionally substituted by one or more fluoro atoms);
R8 represents -N(R5c)R5d or -C1-4 alkyl optionally substituted by one or more substituents selected from halo (e.g. F) and -0-CH3;
R5c and R5d independently represent H, C1-6 alkyl or R5c and R5d are linked together to form a 3- to 6-membered ring; and/or R9a, R9b, R9c, R9d and R9e independently represent H, halo or C1-4 alkyl.
In an embodiment, ring A is represented as follow:

-15--r----'.- N-.\= .r.----N)k r'¨'NA' R1 ) R1 ,.......õ.., N .....,L)/ R1 L.....,..),.."
__________________________________________ N A. 1 -"--.'N-\
R1 4., v_ i R =
wherein R1 represents one or more optional substituents as hereinbefore defined (and independently selected).
In another embodiment, ring A is represented as follow:
Riatili) Ritr)Niki Ria ....q.) RA..
i....ar,.. N
..,.
Rib N)''"/
Ric (II) (III) (IV) (V) (VI) R1 a Rib Rib )/
r4; cic,)õ. crN'IsAi /
N 1\l R1a-s7\---1 (VII) (VIII) (IX) (X) (XI) In an embodiment, the combined ring system, i.e. ring A fused to the 5-membered ring containing two nitrogen atoms may be represented as follow:

\ 2 N 2 R ______________________________________ R R ______ R R __________ R
N N
00s 0 0 Ri ________________________________________________ \ 2 R1 31.217¨VR 2 R RI ____ \ R2 W S N
wherein It' represents one or more optional substituents as hereinbefore defined (and independently selected). In another embodiment, the combined ring system may be represented as follow:

\ R = ____________________________________ R2 RI ___ cR2 N N
In an embodiment, ring B is represented as follow:
555 5\ N N S
I I el I
g ----s 00(11) 0001) OM V) (XXV) II >1 II ___ NN N "NO
(>0(V I ) (XXVI I) (ON111) (XXIX) wherein the right-hand side of (XXII) to (XXIX) is connected to the ring C.
In an embodiment, ring C is represented as follows:

N N NTh N R3 r( N N
--N N ss R3 R3 (XXX) (=CI) (XXXII) In an embodiment, rings A and C may be represented within the general formula as follows:

N
N "Th N---( I

(XXXIII) and integers RI, R2, R3, XI, X2 and X3 are as hereinbefore defined.
In an embodiment, rings A, B and C may be represented as follows:

\i\I ---\NxILNN. \1*---N7N v -1 --( I H L)------ce51.,.,, Ns-R3 WOK I V) N S

NI
_.N ( -- N ...'') () S--1 1\11-L-NLR3 <XXV) N

\i \I - - -Ix iL N
I H L ?-----N.,..,/ N ,, R- ()(XXV I ) N N

-----\11.e.N N---NV----1 (X)(XV I I) N( I H )N R3 N-1 i VXXVIII) NN

R
KN-1-L.7N ()O<XIX) N = 3 N ()<XXX) N---( H
S N., h0 \IL
N-1 i < (XXXX I ) and integers R1, R2 and R3 are as hereinbefore defined.
In an embodiment, compounds of the invention include those in which:
RI represents one or more substituents selected from halo, C1-4 alkyl, -OCI-4 alkyl, -N(R5a)R5b; or any two RI groups may be taken together (when attached to adjacent atoms of the A ring) to form a 5- or 6-membered ring optionally containing one or two heteroatoms, and which ring is optionally substituted by one Of two C1-3 alkyl substituents; and/or R5a and R5b independently represent hydrogen or C1-3 alkyl.
In another embodiment, compounds of the invention include those in which:

RI represents one or more substituents selected from halo (e.g. fluoro or chloro), C1-4 alkyl (which may be straight-chain, so forming e.g. methyl or isopropyl, or, cyclic, so forming e.g. cyclopropyl), -0C1_2 alkyl (so forming e.g. a -OCH3 group), -NH2, -N(H)(Ci_l alkyl) (so forming e.g. a NHCH3 group), or, two RI groups may be adjacent to each other and may be linked to form a 5- or 6-membered ring optionally containing one or two (e.g. one) heteroatom(s) (so forming e.g. a cyclopentyl moiety or a tetrahydropyranyl moiety).
In an embodiment, compounds of the invention include those in which:
R2 represents C1-3 alkyl optionally substituted by one or more fluoro atoms, so forming e.g. -CH3, -CH2CH3, cyclopropyl, -CHF2 or CF3.
In an embodiment, or in several embodiments:
-IV represents H, -R7a, -C(=0)-R7h or -SO2-R8;
lea represents C1_3 alkyl optionally substituted by one or two (e.g. one) substituent(s) selected from -0C1_2 alkyl and -CN (so forming for example unsubstituted methyl or a -CH2-C1-11-0CH3 or -CH2-CH2-CN group);
Ieb represents C1-3 alkyl (e.g. methyl);
R8 represents -N(R5')R5d or -C1_4 alkyl optionally substituted by one or more fluoro atoms; and/or R5' and R5d independently represent C1_3 alkyl (e.g. methyl), or, are linked together to form a 3- to 6-membered ring (e.g. a 5-membered pyrrolidinyl ring)_ In a particular embodiment R3 represents -S02-1e. In a further embodiment when represents -S02-R8, then R8 represents C1-2 alkyl optionally substituted by one or more fluoro atoms. In a specific embodment, R3 represents -S02CF3.
PHARMACOLOGY
The compounds according to the invention have surprisingly been shown to be suitable for the treatment of a bacterial infection including a mycobacterial infection, particularly those diseases caused by pathogenic mycobacteria such as Mycobacterium tuberculosis (including the latent and drug resistant form thereof). The present invention thus also relates to compounds of the invention as defined hereinabove, for use as a medicine, in particular for use as a medicine for the treatment of a bacterial infection including a mycobacterial infection.

Such compounds of the invention may act by interfering with ATP synthase in M.

tuberculosis, with the inhibition of cytochrome bci activity being the primary mode of action. Cytochrome bci is an essential component of the electron transport chain required for ATP synthesis.
Further, the present invention also relates to the use of a compound of the invention, as well as any of the pharmaceutical compositions thereof as described hereinafter for the manufacture of a medicament for the treatment of a bacterial infection including a mycobacterial infection.
Accordingly, in another aspect, the invention provides a method of treating a patient suffering from, or at risk of, a bacterial infection, including a mycobacterial infection, which comprises administering to the patient a therapeutically effective amount of a compound or pharmaceutical composition according to the invention.
The compounds of the present invention also show activity against resistant bacterial strains.
Whenever used hereinbefore or hereinafter, that the compounds can treat a bacterial infection it is meant that the compounds can treat an infection with one or more bacterial strains.
The invention also relates to a composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound according to the invention. The compounds according to the invention may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, in particular, for administration orally or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets.
Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations.
Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 % by weight, more preferably from 0.1 to 70 % by weight, even more preferably from 0.1 to 50 % by weight of the active ingredient(s), and, from 1 to 99.95 % by weight, more preferably from 30 to 99.9 % by weight, even more preferably from 50 to 99.9 % by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.
The pharmaceutical composition may additionally contain various other ingredients known in the art, for example, a lubricant, stabilising agent, buffering agent, emulsifying agent, viscosity-regulating agent, surfactant, preservative, flavouring or colorant.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage.
Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof The daily dosage of the compound according to the invention will, of course, vary with the compound employed, the mode of administration, the treatment desired and the mycobacterial disease indicated. However, in general, satisfactory results will be obtained when the compound according to the invention is administered at a daily dosage not exceeding 1 gram, e.g. in the range from 10 to 50 mg/kg body weight.

Given the fact that the compounds of formula (Ia) or Formula (Ib) are active against bacterial infections, the present compounds may be combined with other antibacterial agents in order to effectively combat bacterial infections.
Therefore, the present invention also relates to a combination of (a) a compound according to the invention, and (b) one or more other antibacterial agents.
The present invention also relates to a combination of (a) a compound according to the invention, and (b) one or more other antibacterial agents, for use as a medicine.
The present invention also relates to the use of a combination or pharmaceutical composition as defined directly above for the treatment of a bacterial infection.
A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of (a) a compound according to the invention, and (b) one or more other antibacterial agents, is also comprised by the present invention.
The weight ratio of (a) the compound according to the invention and (b) the other antibacterial agent(s) when given as a combination may be determined by the person skilled in the art. Said ratio and the exact dosage and frequency of administration depends on the particular compound according to the invention and the other antibacterial agent(s) used, the particular condition being treated, the severity of the condition being treated, the age, weight, gender, diet, time of administration and general physical condition of the particular patient, the mode of administration as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that the effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. A
particular weight ratio for the present compound of the invention and another antibacterial agent may range from 1/10 to 10/1, more in particular from 1/5 to 5/1, even more in particular from 1/3 to 3/1.
The compounds according to the invention and the one or more other antibacterial agents may be combined in a single preparation or they may be formulated in separate preparations so that they can be administered simultaneously, separately or sequentially. Thus, the present invention also relates to a product containing (a) a compound according to the invention, and (b) one or more other antibacterial agents, as a combined preparation for simultaneous, separate or sequential use in the treatment of a bacterial infection.
The other antibacterial agents which may be combined with the compounds of the invention are for example antibacterial agents known in the art. For example, the compounds of the invention may be combined with antibacterial agents known to interfere with the respiratory chain of Mycobacterium tuberculosis, including for example direct inhibitors of the ATP synthase (e.g. bedaquiline, bedaquiline fumarate or any other compounds that may have be disclosed in the prior art, e.g.
compounds disclosed in W02004/011436), inhibitors of ndh2 (e.g. clofazimine) and inhibitors of cytochrome bd. Additional mycobacterial agents which may be combined with the compounds of the invention are for example rifampicin (=rifampin); isoniazid;
pyrazinami de; amikacin ; ethi on ami de; ethambutol ; streptomycin; p ara-ami n os al i cyli acid; cycloserine; capreomycin; kanamycin; thioacetazone; PA-824; delamanid;
quinolones/fluoroquinolones such as for example moxifloxacin, gatifloxacin, ofloxacin, ciprofloxacin, sparfloxacin; macrolides such as for example clarithromycin, amoxycillin with clavulanic acid; rifamycins; rifabutin; rifapentin; as well as others, which are currently being developed (but may not yet be on the market; see e.g.
http://www.newtbdrugs.org/pipclinc.php).
Compounds of the invention (including forms and compositions/combinations comprising compounds of the invention) may have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the above-stated indications or otherwise. For instance compounds of the invention may advantages associated with:
lower cardiotoxicity; no reactive metabolite formation (e.g. that may cause toxicity issues, e.g. genotoxicity); no formation of degradants (e.g. that are undesired or may elicit unwanted side-effects); and/or faster oral absorption and improved bioavailability.
GENERAL PREPARATION
The compounds according to the invention can generally be prepared by a succession of steps, each of which may be known to the skilled person or described herein.

EXPERIMENTAL PART
Compounds of formula I may be prepared in accordance with the techniques employed in the examples hereinafter (and those methods know by those skilled in the art), for example by using the following techniques.
Compounds of formula (I) may be prepared by:
(i) reaction of a compound of formula (XXXXII), R1r \ R2 (OOKX1 I ) in which the integers are hereinbefore defined, with a compound of formula (XXXXIII), H NJo) <
Xi N R4 (000(11 I) wherein the integers are as hereinbefore defined, which reaction may be performed in the presence of a suitable coupling reagent, for instance selected from diisopropylethylamine (DIPEA), 14bis(dimethylamino)methyleneJ-1H-1,2,3-triazolo[4,5-blpyridinium-3-oxid bexafluorophosphate (HATU), 1 -(3-dimethylaminopropy1)-3-ethylcarbodiimide (EDCI), 1-hydroxybenzotriazole (HOBt), 0-(benzotriazole-1-y1)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), or a combination thereof, unders suitable conditions such as those described in the examples hereinafter; for example, in the presence of a suitable coupling reagent (e.g.
1,1'-carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropy1)-ethylcarbodiimide (or hydrochloride thereof) or N,N'-disuccinimidyl carbonate), optionally in the presence of a suitable base (e.g. sodium hydride, sodium bicarbonate, potassium carbonate, pyridine, triethylamine, dimethylaminopyridine, diisopropylamine, sodium hydroxide, potassium tert-butoxide and/or lithium diisopropylamide (or variants thereof) and an appropriate solvent (e.g.
tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide, trifluoromethylbenzene, dioxane or triethylamine). Alternatively, the carboxylic acid group of the compound of formula (XIV) may first be converted under standard conditions to the corresponding acyl chloride (e.g. in the presence of P0C13, PC15, SOC12 or oxalyl chloride), which acyl chloride is then reacted with a compound of formula (XV), for example under similar conditions to those mentioned above;
(ii) coupling of a compound of formula (XXXX1V), \ I

(XX,XXI V) wherein the integers are as hereinbefore defined, and R13 represents a suitable group, e.g. a suitable leaving group such as chloro, bromo, iodo or a sulfonate group (for example a type of group that may be deployed for a coupling), with a compound of formula (XXXXV), 4 X4, N
X5=0 xk (XXXXV) wherein R3 is as hereinbefore defined, and R34 represents a suitable group, e.g. a suitable leaving group under standard conditions, for example optionally in the presence of an appropriate metal catalyst (or a salt or complex thereof) such as Pd(dba)2, Pd(OAc)2, Cu, Cu(OAc)2, Cut, NiC12 or the like, with an optional additive such as Ph3P. X-phos or the like, in the presence of an appropriate base (e.g.
t-BuONa, or the like) in a suitable solvent (e.g. dioxane or the like) under reaction conditions known to those skilled in the art.
It will be appreciated by those skilled in the art that some compounds of formula (I) may be converted to other compounds of formula (I).
It is evident that in the foregoing and in the following reactions, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art, such as extraction, crystallization and chromatography. It is further evident that reaction products that exist in more than one enantiomeric form, may be isolated from their mixture by known techniques, in particular preparative chromatography, such as preparative HPLC, chiral chromatography. Individual diastereoisomers or individual enantiomers can also be obtained by Supercritical Fluid Chromatography (SCF).
The starting materials and the intermediates are compounds that are either commercially available or may be prepared according to conventional reaction procedures generally known in the art.
Examples 1. General Information Melting points Melting points were recorded using a differential scanning calorimeter DSC 1 Mettler Toledo. Melting points were measured with a temperature gradient of 10 C per min from 25 to 350 C. Values are peak values. Unless indicated, this method is used.
An alternative method is with open capilliary tubes on a Mettler Toledo MP50, which may be indicated at "MT". With this method, melting points are measured with a temperature gradient of 10 C/minute. Maximum temperature is 300 C. The melting point data is read from a digital display and checked from a video recording system.

1I-INMR spectra were recorded on a Bruker Avance DRX 400 spectrometer or Bruker Advance III 400 spectrometer using internal deuterium lock and equipped with reverse double-resonance (1H, 13C, SEI) probe head with z gradients and operating at MHz for proton and 100 MHz for carbon and a Bruker Avance 500 MHz spectrometer equipped with a Bruker 5mm BBFO probe head with z gradients and operating at MHz for proton and 125 MHz for carbon.
NMR spectra were recorded at ambient temperature unless otherwise stated.
Data are reported as follow: chemical shift in parts per million (ppm) relative to TMS
(6 = 0 ppm) on the scale, integration, multiplicity (s = singulet, d =
doublet, t = triplet, q = quartet, quin = quintuplet, sex = sextuplet, m = multiplet, b = broad, or a combination of these), coupling constant(s) Jr in Hertz (Hz).
HPLC- LCMS
Analytical methods LCIVLS
The mass of some compounds was recorded with LCMS (liquid chromatography mass spectrometry). The methods used are described below.
Genera/ procedure LCMS Methods A and B
The High Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in the respective methods. If necessary, additional detectors were included (see table of methods below). Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time...) in order to obtain ions allowing the identification of the compound's nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software.
Compounds are described by their experimental retention times (Rt) and ions.
If not specified differently in the table of data, the reported molecular ion corresponds to the [M-F1-11+ (protonated molecule) and/or EM-Hr (deprotonated molecule). In case the compound was not directly ionizable the type of adduct is specified (i.e.
[M+NH411, [M+HCOOL etc...). For molecules with multiple isotopic patterns (Br, Cl..), the reported value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used.
Hereinafter, "SQD" means Single Quadrupole Detector, "RT" room temperature, "BEH- bridged ethylsiloxane/silica hybrid, "HSS- High Strength Silica, -DAD-Diode Array Detector, "MSD" Mass Selective Detector.

Table: LCMS Method codes (Flow expressed in mL/min; column temperature (T) in C; Run time in minutes).
Flow Method Column T Run Instrument Column Mobile phase gradient code time Thermoscie Agilent: A: HCOOH 98% A for 2 mm, ntific Poroshe 0.1% in to 0% A in Ultimate 11 EC- water/ min, held for 3.4 A
18.4 3000 DAD C18 B: HCOOH
min, back to 98%
and A in 1.3 min' 30 (4 vim, 0.05% in Brucker 4.6x100 CH3CN
held for 1.7 min HCT ultra mm) YMC-Agilent 2.6 pack From 95% A
to 1100 A: 0.1%
ODS- 5% A in 4.8 min, HPLC HCOOH in AQ C18 held for 1.0 min, 6.2 (50x to 95% A in 0.2 35 LC/MS B: CH3CN
4.6 mm, mm.

3 rim) When a compound is a mixture of isomers which give different peaks in the LCMS
5 method, only the retention time of the main component is given in the LCMS table.
1. Abbreviations (and formulae) AcOH Acetic acid AcC1 Acetyl chloride BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl BrettPhos 2-(Dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl BrettPhos Pd G3 [(2-Di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropy1-1,11-bipheny1)-2-(21-amino-1,1' -biphenyl)lpalladium(II) methanesulfonate methanesulfonate CBr4 Tetrabromomethane CbzCl Benzyl chloroformate CH3CN / ACN Acetonitrile Cs/CO3 Cesium carbonate CSA Camphor-10-sulfonic acid DCE Dichloroethane DCM or CH2C12 Dichloromethane DIPEA N,N-Diisopropylethylamine DMAP 4-(Dimethylamino)pyridine DME 1,2-Dimethoxyethane DMF Dimethylformamide DMF-DMA N,N-dimethylformamide dimethyl acetal DMSO Methyl sulfoxide EDCI=HC1 N-(3-Dimethylaminopropy1)-N'-ethylcarbodiimide hydrochloride Et20 Diethylether Et3N or TEA Triethylamine Et0Ac Ethyl acetate Et0H Ethanol hour H2 Dihydrogen gas HATU Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium HBr Hydrobromic acid HC1 Hydrochloric acid HFIP Hexafluoroisopropanol HOBT=H20 1-Hydroxybenzotriazole hydrate i-PrOH Isopropyl alcohol K2CO3 Potassium carbonate KHSO4 Potassium bisulfate LiBH4 Lithium borohydride LiOH Lithium hydroxide LiHMDS Lithium bis(trimethylsilyl)amide Me0H Methanol Mel Iodomethane MeTHF / 2-MeTHE Methyltetrahydrofurane MgSO4 Magnesium sulfate min Minute N2 Nitrogen NaCl Sodium Chloride NaHCO3 Sodium Bicarbonate NaNO2 Sodium nitrite NaOH Sodium hydroxide NBS 1-bromopyrrolidine-2,5-dione NH3 Ammonia NH4C1 Ammonium, chloride NH4HCO3 Ammonium bicarbonate NMR Nuclear Magnetic Resonance Pd/C Palladium on carbon PdC1/(PPh3)2 Dichlorobis(triphenylphosphine)palladium(II) Pd(OAc)2 Palladium(II) acetate Pd2dba3 Tris(dibenzylideneacetone)dipalladium(0) Pd(PPh3)4 Palladium-tetrakis(triphenylphosphine) Pd(dffp)C12.DCM [1,1r-Bis(diphenylphosphino)ferroceneldichloropalladium(II) complex with dichloromethane PIDA (Diacetoxyiodo)benzene P0C13 Phosphorous Oxychloride Ra-Ni / Ni Raney Raney -Nickel rt / RT Room temperature RuPhos 2-Dicyclohexylphosphino-2',6'-ditsopropoxybiphenvl RuPhos Pd G3 (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-bipheny0[2-(2'-amino-1, I '-biphenyl)] palladium(II) methanesulfonate t-AmylOH tert-Amyl alcohol SiOH Silica Gel TBTU 0-(benzotriazole-1-y1)-N,N,N',N'-tetramethyluronium tetrafluorob orate Tf"20 Trifluoromethanesulfonic Anhydride TFA Trifluoroactetic acid 'VHF Tetrahydrofuran TMSC1 Trimethylsilyl chloride Ts0H or PTSA p-Toluensulfonic acid AlMe3 Trimethylaluminium BH3 1M in THF Borane tetrahydrofuran complex solution 1.0 M in THF
CBrC13 Bromotrichloromethane Boc20 Di-tert-butyl dicarbonate KOAc Potassium acetate K3PO4.H20 Hydrated tripotassiurn phosphate KFIC03 Potassium hydrogen carbonate Synthesis of compound 1 HBr 48% in water, 1-120 1M in DCM, NaNO2, AcOH, LiB114, Et0H Et N. dry DCM, N No=%.
H2N¨'1 water, 0 C, 4 h Br¨fN I I
S.A.s.soN 50 C, 5 h Br N I I
0 C to RT, 18h CAS [88002-33-9] A-1 A-2 BOC-11-0¨B::t N HCI 4M in dioxane, Br_tJC1NOCF CAS [330794-35-9], 1-04-- LN CF DCM, 0 C to RT, 3h /-044N:LN,Cis...CF3 BOC¨N N 'S' N2N
K,PO4.H,0 .HCI
Pd(dppf)CI, A-3 Hp, dioxane, A-4 100 C, 3 h COOH
HATU, DIPEA, 0 CF3 DMF, RT, 18 h CIcztiN

.HCI
CAS [1216142-18-5] A-5 compound 1 Preparation of compound A-1 To an argon-purged mixture of11,2,41Triazolo11,5-alpyrazin-2-amine (CAS 188002-33-91, 1.00 g, 7.40 mmol) in acetic acid (6.3 mL) were added successively Hydrobromic acid 48% in water (4.19 mL. 37.0 mmol) and a solution of Sodium nitrite (613 mg, 8.88 mmol, 1.2 eq.) in water (5.3 mL) at 0 C. The reaction mixture was stirred for 1 hat 0 C. A solution of sodium nitrite (511 mg, 7.40 mmol, 1 eq.) in water (4.4 mL) was added at 0 C and the reaction mixture was stin-ed for 3 h at 0 C. The reaction mixture was concentrated under reduced pressure and partitioned between water (100 mL) and Et0Ac (100 mL). The layers were separated, and the aqueous layer was extracted with Et0Ac (2 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford an orange oil. This was purified by flash chromatography over silica gel (irregular SiOH, Cyclohexane/Et0Ac from 100/0 to 50/50 over 55 min) to afford a white solid which was triturated with Et20 (3 mL) to afford intermediate A-1 as a white solid, 0.63 g (43%).

Preparation of intermediate A-2 To an argon-purged mixture of A-1 (500 mg, 2.51 mmol) in Ethanol (22 mL) was added Lithium borohydride (219 mg, 10.0 mmol) at room temperature. The reaction mixture was stirred at 50 C for 5 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was quenched with a 1.0 M aq. HC1 solution (pH ¨1, 30 mL) and extracted with Et0Ac (2 x 100 mL). The aqueous layer was basified with a saturated aqueous Na2CO3 solution and extracted with DCM (3 x mL). The combined organic layers were washed with brine (150 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford intermediate A-2 as a white solid, 0.36 g (71%, the crude was used such as in the next step).
Preparation of intermediate A-3 To a solution of A-2 (340 mg, 1.68 mmol) and triethylamine (0.700 mL, 5.02 mmol) in DCM (10 mL) was added 1M Trifluoromethanesulfonic anhydride solution in DCM
(3.35 mL, 3.35 mmol) dropwise at 0 C. The reaction mixture was allowed to warm to room temperature and stirred for 18 h. Water (15 mL) and DCM (15 mL) were added to the reaction mixture and the layers were separated. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford a brown gum. This was triturated with Et20 (2x 2 mL) to afford intermediate A-3 as a brown solid, 0.506 g (90%).
Preparation of intermediate A-4 An argon-purged mixture of A-3 (506 mg, 1.51 mmol), 4-(tert-Butoxycarbonylaminomethyl) phenylboronic acid, pinacol ester (604 mg, 1.81 mmol), potassium phosphate monohydrate (1.04 g, 4.53 mmol) and [1.1'-Bis(diphenylphosphino)ferrocene] dichloropalladium (111 mg, 0.151 mmol) in 1,4-dioxane (7.5 mL) and water (1.5 mL) was stirred at 100 C for 3 h. The reaction mixture was cooled to room temperature, filtered on celitek and washed with Et0Ac (50 mL) to afford a brown gum. A purification was carried out by flash chromatography over silica gel (irregular SiOH, Cyclohexane/Et0Ac from 100/0 to 50/50 over 50 mm) to afford of intermediate A-4 as a yellowish solid, 0.51 g (73%).

Preparation of intermediate A-5 To an argon-purged mixture of A-4 (500 mg, 1.08 mmol) in DCM (2 mL) was added 4M solution of HC1 in 1,4-dioxane (2.71 mL, 10.8 mmol) at 0 C. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. The reaction mixture was concentrated under reduced pressure to afford intermediate A-5 as a white solid, 0.42 g (97%).
Preparation of compound 1 To an argon-purged mixture of 6-Chloro-2-ethylimidazo[1,2-a1pyridine-3-carboxylic acid (CAS [1216142-18-5], 99.8 mg, 0.444 mmol) in DMF (6 mL) was added HATU
(203 mg, 0.533 mmol) at room temperature. The reaction mixture was stirred for minutes at room temperature before the addition of A-5 (212 mg, 0.533 mmol) and DIPEA (0.309 mL, 1.78 mmol). The resulting mixture was stirred at room temperature for 16 h and poured into water (20 mL). The resulting precipitate was filtered on a glass-frit, washed with water (3 x 20 mL) and dried under vacuum at 60 C to afford a brown solid. A purification was carried out by flash chromatography over silica gel (irregular SiOH, DCM/Me0H from 100/0 to 95/5 over 45 min) to afford a brownish solid. This was triturated with Me0H (2 mL) and vacuum-dried at 60 C for 48 h to afford compound 1 as a beige solid, 0.12 g (48%).
'H NMR (400 MHz, DMSO-d6) 6 ppm 9.10 (d, J = 1.7 Hz, 1H), 8.53 (t, J = 5.9 Hz, 1H), 7.97 (d, J = 8.2 Hz, 2H), 7.68 (d, J = 9.5 Hz, 1H), 7.48 (d, J = 8.2 Hz, 2H), 7.47 (dd, J = 9.5 Hz, 2.1 Hz, 1H), 4.96 (s, 2H), 4.59 (d, J = 5.9 Hz, 2H), 4.36 (t, J = 5.4 Hz, 2H), 4.15 (t, J = 5.2 Hz, 2H), 3.02 (q, J = 7.5 Hz, 2H), 1.27 (t, J = 7.5 Hz, 3H).
Synthesis of compound 2 COOH H2N NICN..CF3 HATU, DIPEA, 0õ
0 DMF, RT, 18 h CI
(N=IN\

CAS [2059140-68-8] A-5 compound 2 Accordingly, compound 2 was prepared in the same way as compound 1 starting from 6-Chloro-2-ethylimidazo[1,2-alpyrimidine-3-carboxylic acid CAS [2059140-68-8]

(0.39 mmol) and intermediate A-5 (0.46 mmol) yielding 0.13g (57%) as a white powder.
IHNMR (400 MHz, DMSO-d6) 6 ppm 9.43 (d, J = 2.6 Hz, 1H), 8.69 (d, J = 2.6 Hz, 1H), 8.63 (t, J = 6.0 Hz, 1H), 7.97 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H), 4.96 (s, 2H), 4.59 (d, J = 5.9 Hz, 2H), 4.36 (t, J = 5.3 Hz, 2H), 4.15 (t, J = 5.3 Hz, 2H), 3.05 (q, J = 7.5 Hz, 2H), 1.29 (t, J = 7.5 Hz, 3H).
Synthesis of compound 4 NC ..A., F _ Bis(pinacolato)diboiron 141j BH3 1M in THF H2N 40 F Bocp, E% BOC
N, ,Iii del F
KoA , pu (amc p 2, THF, 80C, 1h I dry DCM, RT, 3.5 h, dioxane, 90 C, ISO
Br ______________________________________________________________________ 1 Br .1111111F Br CAS [133059-44-6] B-1 B-2 BOC Dr-eN:x04,cFs F
F
il . F N
0 HCIcm4M0 cicn tdomRsTa dioxane, 1_641..õN/N.) 0 A-3 0 Noi.,......N,g..CF, D ' iii...
________________________________ a. BOC-N a. 1-ir K31,04.H20 H 0 Pd(dppf)Cl2 .HCI
B-3 H20, dioxane, B4 100 C, 17 h F
FN..., COON
CI,,..,.
0 /-6-1:101......õNii CF
11):11.4111-1 - " ...1_64 N.."..1 wit......õ.N.jj...CF3 HATU, DIPEA, DMF, RT, 180 , CI tl S-.HCI 0 compound 4 CAS [2069140 68 8]
Preparation of intermediate B-1 To a solution of 4-Bromo-3-fluorobenzonitrile (CAS [133059-44-6], 2.00 g, 10.0 mmol) in THF (8 mL) was added Borane tetrahydrofuran complex in THF (1M) (30.0 mL, 30.0 mmol) at room temperature. The reaction mixture was stirred at 80 C
for 1 h.
The reaction mixture was quenched with Me0H (20 mL) and stirred for 10 mm, then concentrated under reduced pressure to afford a yellow oil, 2.51 g (quantitative), used as such without further purifications.
Preparation of intermediate B-2 To a solution of B-1 (2.40 g, 9.56 mmol) and triethylamine (4.00 mL, 28.7 mmol) in DCM (60 mL) was added Di-tert-butyl dicarbonate (2.19g. 10.0 mmol) at 15 'V, then the reaction mixture was stirred at room temperature for 3.5 h. The reaction mixture was concentrated under reduced pressure to afford a sticky oil (3.7 g). The crude was purified by flash chromatography over silica gel (irregular SiOH, eluent: from 4 to 36 % of Et0Ac in Cyclohexane) affording intermediate B-2 after vacuum-drying at for 17 has a white solid, 2.17 g (75%).
Preparation of intermediate B-3 To a N2 purged solution of B-2 (1.92g. 6.31 mmol), Bis(pinacolato)diboron (1.92g.
7.58 mmol) and Potassium acetate (1.55 g, 15.8 mmol) in 1,4-dioxane (31 mL) was added [1,1'-Bis(diphenylphosphino)ferrocene] dichloropalladium(II) (462 mg, 0.631 mmol), then the reaction mixture was stirred at 90 'V for 18 h. The reaction mixture was filtered on celite , the filter cake was rinsed with Et0Ac (-20 mL) and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel (irregular SiOH, 3 to 30 % of Et0Ac in Cyclohexane) to afford intermediate B-3 as a colourless oil which crystalized on standing over time as a white solid, 1.3 g (60%).
Preparation of intermediate B-4 A N2-purged mixture of intermediate A-3 (300 mg, 0.895 mmol), B-3 (377 mg, 1.07 mmol), Potassium phosphate tribasic monohydrate (618 mg, 2.69 mmol) and 1, I:-Bis(diphenylphosphino) ferrocene dichloropalladium (II) (65.5 mg, 0.090 mmol) in 1,4-dioxane (3.6 mL) and water (0.9 mL) was stirred at 100 "V for 17 h. The reaction mixture was cooled to rt, filtered on celite0 and the filter cake was washed with Et0Ac (50 mL). The filtrate was concentrated and purified by flash chromatography over silica gel (irregular SiOH, Cyclohexane/Et0Ac from 94/6 to 50/50 over 30 min) to afford intermediate B-4 as a white solid, 0.28 g (65%).
Preparation of intermediate B-5 To a nitrogen-purged mixture of B-4 (280 mg, 0.584 mmol) in dry DCM (1.2 mL) was added 4M solution of HCl in 1,4-dioxane (1.46 mL, 5.84 mmol) at 0 C. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. The reaction mixture was concentrated under reduced pressure to afford intermediate B-5 as a white solid, 0.243 g (quantitative).

Preparation of compound 4 Accordingly, compound 4 was prepared in the same way as compound 1 starting from 6-Chloro-2-ethylimidazo[1,2-alpyrimidine-3-carboxylic acid CAS [2059140-68-8]
(0.4 mmol) and intermediate B-5 (0.48 mmol) yielding 0.13g (57%) as a white powder.
1HNMR (500 MHz, DMSO-d6) 6 ppm 9.44 (d, J = 2.7 Hz, 1H), 8.70 (d, J = 2.7 Hz, 1H), 8.65 (t, J = 6.0 Hz, 1H), 7.97 (t, J = 8.0 Hz, 1H), 7.37-7.31 (m, 2H), 4.97 (s, 2H), 4.60 (d, J = 5.9 Hz, 2H), 4.39 (t, J = 5.5 Hz, 2H), 4.16 (t, J = 5.0 Hz, 2H), 3.06 (q, J =
7.5 Hz, 2H), 1.30 (t, J = 7.5 Hz, 3H).
Synthesis of compound 7 COOH

HATU, DIPEA, INN-j..õN CF DMF, H2N RT, 18 h .HCI

compound 7 Accordingly, compound 7 was prepared in the same way as compound 1 starting from intermediate AI-3 (0.72 mmol) and intermediate B-5 (0.45 mmol) yielding 0.084g (32%) as a white powder.
1H NMR (400 MHz, DMSO) 5 9.22 - 9.13 (m, 1H), 8.56 - 8.46 (m, 2H), 7.96 (t, J
=
7.8 Hz, 1H), 7.36 - 7.27 (m, 2H), 4.97 (s, 2H), 4.59 (d, J = 5.9 Hz, 2H), 4.38 (t, J = 5.4 Hz, 2H), 4.16 (t, J = 5.2 Hz, 2H), 3.03 (q, J = 7.5 Hz, 2H), 2.34 (s, 3H), 1.29 (t, J = 7.5 Hz, 3H).

Synthesis of compound 8 C00Et COOH
Cl)rN 0 0 PIDA, DF3=Et20 C I II HNaOH,0 40 .Ect 01HCI
H2 6, h Me-THF, RT, 48h IL
NN N
N
CAS [40439-76-7] AT-1 H2 N''¨'',. g_CF, HATU, DIPE8A, 0 0 DMF, RT, 1 h ..rjzt.C1 N N
compound 8 Preparation of intermediate AT-1 To a solution of 5-chloro-4-methylpyrimidin-2-amine (CAS [40439-76-7], 1 g, 6.97 mmol) in Me-THF (33 mL) at 0 C were added iodobenzene diacetate (2.24 g, 6.96 mmol) and ethyl 3-oxovalerate (1.66 mL, 11.6 mmol). Then boron trifluoride etherate (91.3 .it, 0.349 mmol) was added dropwise. The solution was stirred at 5 C for 1 h and then at room temperature for 18 h. Et0Ac and water were added. The organic layer was washed with brine, dried (MgSO4),evaporated and purified by preparative LC
(irregular SiOH, 15-40 m, 80 g, liquid loading (DCM) mobile phase gradient: from heptane /
Et0Ac 80:20 to 0:100 over 10 CV) the fractions containing product were evaporated to afford 367 mg of intermediate AT-1 Preparation of intermediate AT-2 A mixture of AT-1 (100 mg, 0.374 mmol), NaOH (45 mg, 1.12 mmol) and Et0H (2 mL) was stirred at room temperature for 2 days. The mixture was evaporated to give 164 mg of intermediate AT-2 (purity was estimated to give a quantitative yield).
Preparation of compound 8 Accordingly, compound 8 was prepared in the same way as compound 7 starting from intermediate AT-2 (0.45 mmol) and intermediate A-5 (0.37 mmol) affording 0.09 g (40%) as white powder.

1H NMR (400 MHz, DMSO) 8 9.37 (s, 1H), 8.53 (brs, 1H), 7.96 (t, J = 8.0 Hz, 1H), 7.35 ¨7.30 (m, 2H), 4.97 (s, 2H), 4.59 (s, 2H), 4.38 (t, J = 5.4 Hz, 2H), 4.16 (t, J = 5.3 Hz, 2H), 3.03 (q, J = 7.5 Hz, 2H), 2.62 (s, 3H), 1.28 (t, J = 7.5 Hz, 3H).
Synthesis of compound 21 COOEt COON
0 0 PIDA, BF 3.Et 20 CI Na0H, Et0H, CI'Cri "\./11\Acio'\. Me-THF, RT, 48h µ`..circ H20, 40 C,16h Cl'ac CAS [20712-16-7] CAS [4949-44-4] AL-1 H2N CF, HATU, DIPEA, 0 DMF, RT, 18 hCI., = 1N -LN3s'CF3 ________________________ 3.
compound 21 Preparation of intermediate AL-1 To a solution of 2-Amino-5-chloro-3-fluoropyridine (CAS [20712-16-7J, 2.50 g, 17.1 mmol) in 2-MeTHF (75 mL) at 5 C under N2 were added Ethyl propionylacetate (2.5 mL, 17.6 mmol), Iodobenzene diacetate (5.50 g, 17_1 mmol) and Boron trifluoride diethyl etherate (105 pi, 0.851 mmol) the reaction was stirred at 5 C for 30 min then at room temperature for 18 h. An extra amount of Ethyl propionylacetate (1.25 mL, 8.77 mmol), Iodobenzene diacetate (2.75 g, 8.54 mmol) and Boron trifluoride diethyl etherate (105 pi, 0.851 mmol) were added and the mixture was stirred at room temperature for 48 h. Et0Ac (150 mL) and water (150 mL) were added. The layers were separated, and the organic layer was washed with a saturated aqueous solution of NaHCO3 (200 mL), brine (2 x 200 mL), dried over Na2SO4, filtered and evaporated to afford 8.40 g as a brown viscous oil. This one was purified via preparative LC
(SiOH, 120 g, 50 nm, Eluent: Cyclohexane/Et0Ac, from 100:00 to 50:50), fractions containing product were collected and evaporated to afford 520 mg of intermediate AJ-1 as an orange paste (11%).

Preparation of intermediate AL-2 To a solution of AL-1 (480 mg, 1.77 mmol) in water (9 mL) and Et0H (9 mL) was added NaOH (213 mg, 5.33 mmol). The reaction mixture was stirred for 3 h at 30 C.
The crude was washed with DCM (30 mL) and with Et0Ac (30 mL), the aqueous phase was acidified with an aqueous solution of HC1 (3N) until pH = 2, extracted with DCM (2 x 50 mL). The layers were separated, and the organic layer was dried over Na2SO4, filtered and evaporated to afford 260 mg of intermediate AL-2 as a pale pink solid (60%).
Preparation of compound 21 Accordingly, compound 21 was prepared in the same way as compound 7 starting from intermediate AL-2 (0.72 mmol) and intermediate A-5 (0.45 mmol) affording 0.084 g (32%) as white solid.
'HNMR (400 MHz, DMSO) 8 9.22 ¨ 9.13 (m, 1H), 8.56 ¨ 8.46 (m, 2H), 7.96 (t, J =
7.8 Hz, 1H), 7.36 ¨ 7.27 (m, 2H), 4.97 (s, 2H), 4.59 (d, J = 5.9 Hz, 2H), 4.38 (t, J = 5.4 Hz, 2H), 4.16 (t, J = 5.2 Hz, 2H), 3.03 (q, J = 7.5 Hz, 2H), 2.34 (s, 3H), 1.29 (t, J = 7.5 Hz, 3H).
Synthesis of compound 22 FOH * HATU, DIPEA, = CF3 DMF, RT, 18 h N===== N,g__CF3 CAS [1368682-64-7] A-6 compound 22 Accordingly, compound 22 was prepared in the same way as compound 7 starting from 2-ethy1-6-fluoroimidazo[1,2-alpyridine-3-carboxylic acid (CAS [1368682-64-7], 0.41 mmol) and intermediate A-5 (0.33 mmol) affording 0.084 g (46%) as white solid.
1HNMR (400 MHz, DMSO) 8 9.10¨ 9.03 (m, 1H), 8.48 (t, J = 6.0 Hz, 1H), 7.98 (d, J
= 8.2 Hz, 2H), 7.70 (dd, J = 9.8, 5.4 Hz, 1H), 7.53 ¨ 7.46 (m, 3H), 4.97 (s, 2H), 4.60 (d, J = 5.9 Hz, 2H), 4.37 (t, J = 5.4 Hz, 2H), 4.25 ¨ 4.08 (m, 2H), 3.03 (q, J =
7.5 Hz, 2H), 1.28 (t, J = 7.5 Hz, 3H).

Synthesis of compound 23 COOEt COOH
0 0 PIDA, BF 3.Et,0 Na0H, Et0H, * Me-THF, RT, 48h o s's H2 0 40 C 16h ____________________________________________________________________ mo=

CAS [57963-11-8] AP-1 HATU, DIPEA, 0 = /140CF3 DMF, RT, 18 h compound 23 Preparation of intermediate AP-1 Accordingly, intermediate AP-1 was prepared in the same way as AL-1 starting from 4,5-dimethylpyridin-2-amine (CAS 157963-11-81, 4.09 mmol) and ethyl 3-oxovalerate (CAS [4949-44-41) giving 0.73 g (72%) as white solid.
Preparation of intermediate AP-2 Accordingly, intermediate AP-2 was prepared in the same way as intermediate AL-starting from intermediate AP-1 (0.81 mmol) giving 0.3 g (quantitative).
Preparation of compound 23 Accordingly, compound 23 was prepared in the same way as compound 7 starting from intermediate AP-2 (0.46 mmol) and intermediate A-5 (0.36 mmol) affording 0.110 g (54%) as white powder.
1H NMR (400 MHz, DMSO) 6 8.80 (s, 1H), 8.30 (t, J = 6.0 Hz, 1H), 7.97 (d, J =
8.2 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 7.38 (s, 1H), 4.96 (s, 2H), 4.57 (d, J =
5.9 Hz, 2H), 4.36 (t, J = 5.4 Hz, 2H), 4.15 (t, J = 5.2 Hz, 2H), 2.97 (q, J = 7.5 Hz, 2H), 2.31 (s, 3H), 2.22 (s, 3H), 1.25 (t, J = 7.5 Hz, 3H).

Synthesis of compound 24 N-"N HATU, D, 0 = NC

/NCF3 kat.cF318IPEA h tztiN

CAS [1216036-36-0] A-5 compound 24 Accordingly, compound 24 was prepared in the same way as compound 7 starting from 2-ethy1-6-methy1imidazo[1,2-a1pyridine-3-carboxy1ic acid (CAS [1216036-36-0], 0.43 mmol) and intermediate AA-3 (0.33 mmol) affording 0.111 g (61%) as a white solid.
11-1 NMR (400 MHz, DMSO-d6) 8 8.81 (s, 1H), 8.41 (t, J = 5.9 Hz, 1H), 7.97 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 9.1 Hz, 1H), 7.47 (d, J = 8.2 Hz, 2H), 7.25 (dd, J =
9.1, 1.3 Hz, 1H), 4.96 (s, 2H), 4.58 (d, J = 5.9 Hz, 2H), 4.36 (t, J = 5.4 Hz, 2H), 4.15 (t, J = 5.1 Hz, 2H), 2.98 (q, J = 7.5 Hz, 2H), 2.31 (s, 3H), 1.26 (t, J = 7.5 Hz, 3H).
Synthesis of compound 36 COON HATU, DIPEA, 0 /-CH:".01101,2,CF3 DMF, RT, 18 h CAS [1131613-58-5] A-5 compound 36 Accordingly, compound 36 was prepared in the same way as compound 7 starting from 6-ethyl-2-methylimidazo[2,1-b][1,31thiazole-5-carboxylic acid (CAS [1131613-58-51, 0.41 mmol) and intermediate A-5 (0.33 mmol) yielding 0.124 g (68%) as a white powder.
1HNMR (400 MHz, DMSO) 8 8.19 (t, J = 6.0 Hz, 1H), 7.96 (d, J = 8.2 Hz, 2H), 7.92 (d, J = 1.4 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 4.96 (s, 2H), 4.54 (d, J = 5.9 Hz, 2H), 4.42 -4.31 (m, 2H), 4.24 - 4.10 (m, 2H), 2.90 (q, J = 7.5 Hz, 2H), 2.42 (d, J = 1.0 Hz, 3H), 1.23 (t, J = 7.5 Hz, 3H).

Synthesis of compound 28 Cs2CO2, H20 Pd(dppf)C12 COOEt COOEt rr I>jF
toluene, 100 C Na0H, Et0H, COOH

16 h H20, 40 C, 16h K
CAS [2122474-31-9] CAS [1065010-87-8] AB-1 1-0-4'NN:334,cõ
Hz HATU, DIPEA, 0 =

DMF, RT, 18 h N--= Ns g,CF3 ______________________ a.
4rj._ compound 28 Preparation of intermediate AB-1 Potassium cyclopropyltrifluoroborate (0.62 g, 4.19 mmol), cesium carbonate (1.2 g, 3.69 mmol) and Pd(dppf)C17 (0.2 g, 0.25 mmol) were added to a solution of ethyl 6-bromo-2-ethylimidazo[1,2-a]pyrimidine-3-carboxylate (CAS [2142474-31-9] in toluene (25 mL) and water (10 mL) a screw top vial while N2 was bubbling at it The mixture was stirred at 100 'V for 16 h. Water was added, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (SiOH; ethyl acetate in heptane, from 0/100 to 50/50). The desired fractions were collected and concentrated in vacuo to yield intermediate AB-1 as a brown solid (0.35 g, 76%).
Preparation of compound AB-2 Accordingly, intermediate AB-2 was prepared in the same way as intermediate AL-starting from intermediate AB-1 (0.58 mmol) giving 0.17 g (quantitative).
Preparation of compound 28 Accordingly, compound 28 was prepared in the same way as compound 7 starting from intermediate AB-2 (0.58 mmol) and intermediate A-5 (0.37 mmol) yielding 0.17 g (77%) as a white solid.
1H NMR (400 MHz, DMSO) 5 9.06 (d, J = 2.4 Hz, 1H), 8.51 (t, J = 5.9 Hz, 1H), 8.46 (d, J = 2.5 Hz, 1H), 7.97 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 4.96 (s, 2H), 4.58 (d, J = 5.9 Hz, 2H), 4.36 (1, J = 5.4 Hz, 2H), 4.23 ¨4.07 (m, 2H), 3.02 (q, J
= 7.5 Hz, 2H), 2.13 ¨2.02 (m, 1H), 1.27 (t, J = 7.5 Hz, 3H), 1.04 ¨0.97 (m, 2H), 0.82 ¨
0.74 (m, 2H).
Synthesis of compound 29 AlMe3 2M in heptane COOEt Pd(P13113)4 COOEt OOH
Br.r.
r-ky_ THF dry, 65 C, 2 h Na0H, Et0H, H20, 40 C, 16h N
sr).*
N N
CAS [2091027-84-61 AC-1 AC-2 on_ N.Th H, Isr¨N¨f¨%Nrs141."CF3 ei HATU, DIPEA, 0 0 DMF, RT, 18 h Nr.

N
compound 29 Preparation of intermediate AC-1 Trimethylaluminum solution 2M in heptane (2.54 mL, 5.08 mmol) was added dropwise to a solution of ethyl 6-bromo-2-methylimidazo11,2-a]pyrimidine-3-carboxylate (CAS
[2091027-34-6], 0.41 g, 1.12 mmol) and Pd(PPh3)4 (0.084g. 0.073 mmol) in THF
dry (11 mL) in a round bottom flask 2-neck charged with a condenser under nitrogen atmosphere at room temperature. Then the mixture was stirred at 65 C for 2 h.
The mixture was cooled to 0 C and diluted with DCM. Then 10 ml of water was added dropwise. Then MgSO4 powder was added and the mixture was stirred at room temperature for 30 mm. The result was filtered through of pad of celite , washed with ethyl acetate and concentrated in vacuo. The crude product was purified by flash column chromatography (SiOH, 25 g; DCM/Me0H (9:1) in DCM 0/100 to 20/80). The desired fractions were collected and concentrated in vacuo to yield intermediate AC-1 as a yellow solid (0.19 g, 59%).
Preparation of intermediate AC-2 Accordingly, intermediate AC-2 was prepared in the same way as intermediate AL-starting from intermediate AC-1 (0.68 mmol) giving 0.14 g (quantitative).

Preparation of compound 29 Accordingly, compound 29 was prepared in the same way as compound 7 starting from intermediate AC-2 (0.54 mmol) and intermediate A-5 (0.35 mmol) yielding 0.12 g (66%) as a white powder.
1H NMR (400 MHz, DMSO) 8 9.21 (s. 1H), 8.51 (d, J = 1.8 Hz, 1H), 8.46 (t, J =
5.7 Hz, 1H), 8.00 - 7.94 (m, 2H), 7.48 (d, J = 7.3 Hz, 2H), 4.96 (s, 2H), 4.59 (d, J = 5.7 Hz, 2H), 4.37 (t, J = 5.2 Hz, 2H), 4.16 (d, J = 4.9 Hz, 2H), 2.64 (d, J = 1.3 Hz, 3H), 2.34 (s, 3H).
Synthesis of compound 30 COOH N

DMF, RT, 18 h C 3 HATU, DIPEA, CAS [1369253-79-1] A-5 compound 30 Accordingly, compound 30 was prepared in the same way as compound 7 starting from 2-cyclopropy1-6-methylimidazo111,2-alpyridine-3-carboxylic acid CAS [1369253-79-1]
(0.52 mmol) and intermediate A-5 (0.35 mmol) yielding 0.13 g (65%) as a white powder.
1H NMR (400 MHz, DMSO) 8 8.84 (s, 1H), 8.52 (t, J = 6.0 Hz, 1H), 7.97 (d, J =
8.2 Hz, 2H), 7.47 (dd, J = 11.9, 8.7 Hz, 3H), 7.23 (dd. J = 9.1, 1.5 Hz, 1H), 4.96 (s, 2H), 4.60 (d, J = 5.9 Hz, 2H), 4.36 (t, J = 5.4 Hz, 2H), 4.15 (t, J = 5.1 Hz, 2H), 2.45 -2.37 (m, 1H), 2.30 (s, 3H), 1.00 (d, J = 6.0 Hz, 4H).
Synthesis of compound 31 COOH = HATU, DIPEA, 0 CF DMF, RT, 18 h S' 3 H2N =

CAS [1529528-99-1] A-5 compound 31 Accordingly, compound 31 was prepared in the same way as compound 7 starting from 2-ethyl-5H,6H,7H,8H-imidazo[1,2-a]pyridine-3-carboxylic acid CAS [1529528-99-1]
(0.41 mmol) and intermediate A-5 (0.33 mmol) yielding 0.1 g (57%) as a white solid.

NMR (400 MHz, DMSO) 8 8.27 (t, J = 6.0 Hz, 1H), 7.96 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 8.2 Hz, 2H), 4.96 (s, 2H), 4.47 (d, J = 6.0 Hz, 2H), 4.41 ¨4.33 (m, 2H), 4.22 ¨
4.14 (m, 2H), 4.04¨ 3.95 (m, 2H), 2.74 ¨ 2.69 (m, 2H), 2.65 (q, J = 7.5 Hz, 2H), 1.90 ¨
1.83 (m, 2H), 1.83 ¨ 1.74 (m, 2H), 1.11 (t, J = 7.5 Hz, 3H).
Synthesis of compound 33 COOEt COOH
0 0 CBrCI3, ACN dry, I NaOH, Et0H, KHCO3, 80 C, 2x 16.12 Hp, 40 C, 16h CAS [1193-74-4] AF-1 A-5 N"
HATU, DIPEA, ONN CF

______________________ 3. 0 N--AN
compound 33 Preparation of compound AF-1 Potassium bicarbonate (leq) and Ethyl acetoacetate (1.5eq) were added to a solution of 4,5-dimethy1-2-pyrimidinamine (leq, limiting reagent) in Acetonitrile dry (40eq) in a screw top vial at rt. Then, Bromotricloromethane (3eq) was added at rt and the mixture was stirred at 80 C for 16 h. LCMS analysis showed desired product and starting material. Additional load of Ethyl acetoacetate (0.5 eq), and Bromotricloromethane (leq) were added and the reaction mixture stirred at 80 C for additional 16 h. Saturated aqueous Na1-ICO3 solution was added and the mixture was extracted with Et0Ac (x3).
The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (SiOH, 12 g;
DCM/Me0H 9:1 in DCM 0/100 to 20/80). The desired fractions were collected and concentrated in vacuo to yield intermediate AF-1 as a brown solid (Yield:
26%).
Preparation of intermediate AF-2 Accordingly, intermediate AF-2 was prepared in the same way as intermediate AL-starting from intermediate AF-1 (0.61 mmol) giving 0.13 g (86%).

Preparation of compound 33 Accordingly, compound 33 was prepared in the same way as compound 7 starting from intermediate AF-2 (0.52 mmol) and intermediate A-5 (0.35 mmol) yielding 0.12 g (61%) as a white solid.
IFINMR (400 MHz, DMSO) 5 9.06 (s, 1H), 8.42 (1, J = 6.0 Hz, 1H), 7.96 (d, J =
8.2 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 4.95 (s, 2H), 4.57 (d, J = 5.9 Hz, 2H), 4.36 (t, J = 5.4 Hz, 2H), 4.15 (t, J = 5.3 Hz, 2H), 2.99 (q, J = 7.5 Hz, 2H), 2.27 (s, 3H), 1.26 (t, J = 7.5 Hz, 3H). -CH3 was overlapped with DMSO peak.
Synthesis of compound 34 H2N HATU, DIPEA, = DMF, RT, 18 h \CIN7::HN
" r"
CAS [81438-52-0] A-5 compound 34 Accordingly, compound 34 was prepared in the same way as compound 7 starting from 2,6-Dimethylimidazo[1,2-a[pyridine-3-carboxylic acid CAS [81438-52-0] (0.43 mmol) and intermediate A-5 (0.33 mmol) yielding 0.095 g (54%) as a white solid.
IHNMR (400 MHz, DMSO-d6) 5 8.87 (s, 1H), 8.35 (t, J = 6.0 Hz, 1H), 8.01 - 7.94 (m, 2H), 7.48 (dd, J = 8.6, 4.6 Hz, 3H), 7.25 (dd, J = 9.1, 1.6 Hz, 1H), 4.96 (s, 2H), 4.58 (d, J = 5.9 Hz, 2H), 4.36 (t, J = 5.4 Hz, 2H), 4.15 (t, J = 5.1 Hz, 2H), 2.59 (s, 3H), 2.31 (s, 3H).

Synthesis of compound 42 AIMe2 2M in heptane COOEt Pd(PPh3)4 COOEt BrXj2: 0 0 PIDA, BF 3.Et20 Br THF
dry, Me-THF, RT, 48h N N
CAS [7752-82-1] CAS [24922-02-9] AT-1 H,N N ry,11,CF3 Na0H, Et0H, HATU, DIPEA, 0 'IC 0 N,g,CF3 H20, 40 C, 16h DMF, RT, 18 h N _________________________________________________________ N
AT-3 compound Preparation of intermediate AT-1 In a screw top vial, Boron trifluoride diethyl etherate (0.071 mL, 0.57 mmol) was added dropwise to a solution of 2-Amino-5-bromopyrimidine (CAS [7752-82-1], 1 g, 5.75 mmol), Ethyl-3-cyclopropy1-3-oxopropionate (1.27 mL, 8.62 mmol) and (Diacetoxyiodo)benzene (2.8 g, 8.62 mmol) in 2-MeTHF dry (25 mI.) under nitrogen at rt and the mixture was stirred at 60 C for 16 h. Water was added and the mixture was extracted with Et0Ac. The layers were separated, and the organic layer was washed with saturated aqueous NaHCO3 solution and brine. The combined organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (SiOH, 80 g; Ethyl acetate/Heptane from 0/100 to 25/75). The desired fractions were collected and concentrated in vacuo to yield intermediate AT-1 (0.66 g, 37%) as a yellow solid.
Preparation of intermediate AT-2 Accordingly, intermediate AT-2 was prepared in the same way as intermediate AC-starting from intermediate AT-1 (3.64 mmol) giving 0.73 g (81%).
Preparation of intermediate AT-3 Accordingly, intermediate AT-3 was prepared in the same way as intermediate AL-starting from intermediate AT-2 (0.61 mmol) giving 0.13 g (99%).

Preparation of compound 42 Accordingly, compound 42 was prepared in the same way as compound 7 starting from intermediate AT-3 (0.48 mmol) and intermediate A-5 (0.35 mmol) yielding 0.12 g (61%) as a white solid.
ITINMR (400 MHz, DMSO) 6 9.18 (s, 1H), 8.64 (1, J = 5.8 Hz, 1H), 8.49 (d, J =
2.5 Hz, 1H), 7.97 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 8.3 Hz, 2H), 4.96 (s, 2H), 4.60 (d, J = 5.7 Hz, 2H), 4.36 (t, J = 5.3 Hz, 2H), 4.16 (d, J = 5.1 Hz, 2H), 2.67 (m, 1H), 2.33 (s, 2H), 1.06 (d, J = 6.0 Hz, 4H).
Synthesis of compound 44 Pd(dppCl Cbz¨N 0 z HCI 4M in dioxane, B.P H290:,:dC; t7e , Cb <1*
N'BOC DCM, 0 C to RT, 16h 1¨00'130C H
CAS [1823835-34-2] CAS [1628594-76-2] AG-1 Tf20 1M in DCM, Pd(OH)z, Hz f--0--CONH ::;:irRYT7; ERtOTCµoMrinH, _/=\_;1..y.=====1 0 Cbz¨N Cbz¨ri N.,11,,CF3 __________________ 1-1214N.4".CF3 COOH
N

"".
HATU, DIPEA, DMF, RT, 18 h 17111 0 N compound 44 Preparation of intermediate AG-1 Accordingly, intermediate AG-1 was prepared in the same way as intermediate AE-starting from pyrazine-5(411)-carboxylate (CAS [1823835-34-2], 0.73 mmol) and benzyl 4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yObenzylcarbamate (CAS
[1628594-76-2], 0.88 mmol) affording 0.13 g (35%) as white solid.
Preparation of intermediate AG-2 Accordingly, intermediate AG-2 was prepared in the same way as intermediate AE-starting from AG-1 (0.27 mmol) yielding 0.11 g (100%) as an orange powder.

Preparation of intermediate AG-3 Accordingly, intermediate AG-3 was prepared in the same way as intermediate A-starting from AG-2 (0.27 mmol) yielding 0.06 g (45 %) as white powder.
Preparation of intermediate AG-4 Accordingly, intermediate AG-4 was prepared in the same way as intermediate AE-starting from AG-3 (0.13 mmol) yielding 0.045 g(95%) as white solid.
Preparation of compound 44 Accordingly, compound 44 was prepared in the same way as compound 7 starting from intermediate AG-4 (0.23 mmol) and intermediate A-5 (0.14 mmol) yielding 0.027 g (34%) as a white powder.
1HNMR (400 MHz, DMSO) 6 9.17¨ 9.13 (m, 1H), 8.52¨ 8.46 (m, 2H), 7.75 (d, J =
8.2 Hz, 2H), 7.41 (d, J = 8.3 Hz, 2H), 6.63 (s, 1H), 4.87 (s, 2H), 4.55 (d, J
= 5.9 Hz, 2H), 4.28 (t, J = 5.5 Hz, 2H), 4.10 (t, J = 5.4 Hz, 2H), 3.02 (q, J = 7.5 Hz, 2H), 2.34 (s, 3H), 1.28 (t, J = 7.5 Hz, 3H).
Synthesis of compound 45 COOEt COOH
0 0 PIDA, BF ,,,,Et20 Na0H, water _________________________________________________________________________ cr CiaN Me-THF, 5 C to rt, 48h Et0H, RT, 16h rri_ c( NH
CAS [108990-72-3] CAS [4949-44-4] AD-1 HATU, DIPEA, 0 0 = g=-cF3 DMF, RT, 18 h ______________________ 3. CrNti" 8 compound 45 Preparation of intermediate AD-1 Accordingly, compound AD-1 was prepared in the same way as compound AL-1 starting from 6,7-dihydro-5h-cyclopent4d]pyrimidin-2-amine (CAS [108990-72-3], 7.4 mmol) affording 0.726 g (38%).
Preparation of intermediate AD-2 Accordingly, compound AD-2 was prepared in the same way as compound AL-2 starting from AD-1 (0.77 mmol) affording 0.446 g (44%).
Preparation of compound 45 Accordingly, compound 45 was prepared in the same way as compound 7 starting from intermediate AD-2 (0.60 mmol) and intermediate A-5 (0.38 mmol) affording 0.036 g (16%) as white powder.
NMR (400 MHz, DMS0) 6 9.11 (s, 1H), 8.45 (t, J = 6.0 Hz, 1H), 7.97 (d, J = 8.3 Hz, 2H), 7.47 (d, J = 8.3 Hz, 2H), 4.96 (s, 2H), 4.57 (d, J = 5.9 Hz, 2H), 4.36 (t, J = 5.4 Hz, 2H), 4.15 (1, J = 5.3 Hz, 2H), 3.04 ¨ 2.90 (m, 6H), 2.13 (p, J = 7.6 Hz, 2H), 1.26 (1, J = 7.5 Hz, 3H).
Synthesis of compounds 47, 48 and 51 Preparation of intermediate AI-3 COOEt COOEt Br 0 0 PIDA, BF ?Et p AlMez, Pd(PPh3)4 N
L,NN H2 ))L 0 Me-THF, 60 C THF, 65 C, 1h w*..114 CAS [7752-82-1] CAS [4949-44-4] AI-1 COOH
Na0H, Et0H, Hz0, RT, o.n.

Preparation of intermediate AI-1 2-amino-5-bromopyrimidine (10.0 g; 57.5 mmol) was suspended in dry 2-MeTHF
(250 mL). ethyl 3-oxovalerate (8.2 mL, 57.5 mmol, 1 eq.) and iodobenzene diacetate (18.5 g, 57.5 mmol, 1 eq.) were added. boron trifluoride etherate (0.75 mL, 2.87 mmol, 0.05 eq.) was then added dropwise and the reaction mixture was stirred at 60 C for 1.5 hours. An extra amount of ethyl ethyl 3-oxovalerate (4.10 mL, 28.7 mmol, 0.5 eq.), iodobenzene diacetate (9.25 g, 28.7 mmol, 0.5 eq.) and boron trifluoride etherate (0.75 mL, 2.87 mmol, 0.05 eq.) were added at room temperature and the mixture was stirred at 60 C for lh . The mixture was cooled down to room temperature then Et0Ac and water were added. The organic layer was separated and washed with a saturated solution of NaHCO3 (twice), then with brine (twice). The organic layer was dried over MgSO4, filtered off and concentrated to give 19.7 g as a brown oil. The crude was purified by preparative LC (irregular SiOH, 15-40 um, 330 g, dry loading (SiOH), mobile phase gradient: from DCM 100% to DCM 85%, Et0Ac 15%) to give intermediate AI-1, 9.03 g as yellow crystals (53%).
Preparation of intermediate AI-2 In a sealed tube under N2, to a solution of intemiediate AI-1 (500 mg, 1.68 mmol) and Pd(PPh3)4 (96.9 mg, 0.084 mmol) in THF (12 mL) degassed under N2 was added trimethylaluminum 2m in Hexanes (2 eq., 1.68 mL, 3.35 mmol). The mixture was purged again with N2 and was heated at 65 'V for 1 h. An extra amount of trimethylaluminum 2m in Hexanes (1 eq., 0.839 mL, 1.68 mmol) was added and the mixture was stirred at 65 C for 1 h. The mixture was diluted with DCM, cooled down to 0 C and 1 mL of water was added carefully. The mixture was stirred at room temperature overnight then MgSO4 was added. After 30 min under stirring, the mixture was filtered over a plug of celite and evaporated to give 412 mg of as an orange gum.
The crude was purified by preparative LC (regular SiOH, 30 um, 40 g, dry loading (celite0), mobile phase eluent: Heptane 95%, Et0Ac 5% to Heptane 50%, Et0Ac 50%). Fractions containing product were combined and concentrated to obtain intermediate AI-2, 354 mg of as a yellow gum (90%).
Preparation of intermediate AI-3 To a solution of intermediate AI-2 (120 mg, 0.514 mmol) in water (1 mL) and Et0H (4 mL) was added NaOH (62 mg, 1.55 mmol) and the mixture was stirred at room temperature overnight. The mixture was evaporated then co-evaporated with Et0H
to give intermediate AI-3, 190 mg as a yellow solid. The crude was used as such in next step.

Cs2CO3, z Pd(dppf)CI, Pd(OH), H
H2900,0cd ioixeahne , Et0C, Me0H, RT, 90 min Br ¨eN"'IrTh Cbz¨N N N'BOC
Cbz¨N
CAS [1575613-02-3] CAS [1628594-76-2] AE-1 .014N 0 H2N N,BOC HATU, DIPEA, DMF, RT, 18 h N W 1,11/4=== 13 === '0C HCI 4M
in dioxane, DCM, 0 C to RT, 16h µX=A'N H
AE-2 X=C, CAS [1216036-36-0] X=C, AE-3 X=N, AI-3 X=N, AE-4 . 2HCI
X=C, AE-5 X=N, AE-6 Preparation of intermediate AE-1 In a glass pressure bottle, a stirred mixture of tert-butyl 2-bromo-5,6-dihydro[1,2,41 triazolo[1,5-alpyrazine-7(8H)-carboxylate (CAS [1575613-02-3], 1.02 g, 3.37 mmol), benzyl 4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)benzylcarbamate (CAS
[1628594-76-21, 1.73 g, 4.72 mmol) and [1,1'-Bis(diphenylphosphino)ferroceneldichloropalladium(11), complex with dichloromethane (0.28 g, 0.34 mmol) in dioxane (16 mL) and water (8 mL) while was bubbled with nitrogen. Then Cs2CO3 (2.2 g, 6.75 mmol) was added at room temperature. The mixture was stirred at 90 C for 16 h. The reaction was cooled, diluted with water and extracted with Et0Ac (x3). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (SiOH, 12 g; Et0Ac in Heptane (0/100 to 60/40)).
The desired fractions were collected and concentrated in vacuo to yield intermediate AE-1 as a beige solid (1.34 g, 85%).
Preparation of intermediate AE-2 Palladium hydroxide on carbon (0.2 g, 0.29 mmol) was added to a stirred solution of AE-1 (1.34 g, 2.89 mmol) in Et0Ac (10 mL), and Me0H (3mL) at room temperature under nitrogen atmosphere. Then, nitrogen atmosphere was replaced by H2 (P
atm) and the reaction mixture was stirred at room temperature for 1.5 h. The mixture was filtered through of pad of celite', and solvents was concentrated in vacuo to yield AE-2 as a white solid (0.85 g, 84%).
Preparation of intermediate AE-4 Intermediate AE-2 (0.85 g, 2.57 mmol) was added to a solution of AI-3 (1.08 g, 4.11 mmol), HATU (1.46 g, 3.85 mmol) and DIPEA (3.13 mL, 13.98 mmol) in DMF dry in a round bottom flask at room temperature. The mixture was stirred at room temperature for 16 h. Saturated aqueous NaHCO3 solution was added and the mixture was extracted with Et0Ac (x3). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (SiOH, 25g; DCM/Me0H 9:1 in DCM 0/100 to 20/80). The desired fractions were collected and concentrated in vacuo to yield AE-4 (1.32 g, 95%) as a clear brown solid.
Preparation of intermediate AE-3 Accordingly, intermediate AE-3 is prepared in the same way as intermediate AE-starting from 2-ethyl-6-methylimidazo[1,2-alpyridine-3-carboxylic acid (CAS
[1216036-36-01).
Preparation of intermediate AE-6 HC1 in dioxane (4M) (3.83 mL, 15.33 mmol) was added to a stirred solution of and DCM (20 mL) in a round bottom flask at room temperature. The mixture was stirred at room temperature for 16 h. Solvents were removed in vacuo and the solid was triturated with D1PE to yield AE-6 (1.25 g, qtve) as a beige solid (HC1 salt).
The crude product was used as such in the next step.
Preparation of intermediate AE-5 Accordingly, intermediate AF-5 is prepared in the same way as intermediate AE-starting from intermediate AE-3.

2 __ \
/-0-f14:-I01, compound 47 N õ

Nii-a-fNasNH
DIPEA, DCM
. 2HCI RT, 16 hours ..C.t.14/ = /Nrl,s,0 X=C, AE-5 , H 01'n X=N, AE-6 compound 48 Preparation of compound 47 Pyrrolidine-l-sulfonyl chloride (0.046 mL, 0.27 mmol) was added to a solution of AE-6 (0.12 g, 0.25 mmol) and DIPEA (0.085 mL, 0.49 mmol) in DCM dry (5 mL) in a round bottom flask under nitrogen at room temperature. The mixture was stin-ed at room temperature for 16 h. Saturated aqueous NaHCO3 solution was added and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (SiOH, 12 g; (DCM/Me0H (9:1)) in DCM from 0/100 to 100/0). The desired fractions were collected and concentrated in vacuo. The result was triturated with DIPE and the solid was filtrated to yield 0.057 g of compound 47 as a pale beige solid (42%).
1HNMR (400 MHz, DMSO) 6 9.16 (d, J = 1.2 Hz, 1H), 8.50 (dd, J = 7.7, 4.2 Hz, 2H), 7.96 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 4.63 - 4.49 (m, 4H), 4.27 (t, J = 5.4 Hz, 2H), 3.80 (t, J = 5.4 Hz, 2H), 3.28 (t, J = 6.7 Hz, 4H), 3.02 (q, J = 7.5 Hz, 2H), 2.34 (s, 3H), 1.93 - 1.79 (m, 4H), 1.33 - 1.23 (m, 3H).
Preparation of compound 48 Accordingly, compound 48 was prepared in the same way as compound 47 starting from AE-5 (0.33 mmol) affording 0.12 g (64%).
1HNMR (400 MHz, DMSO) 6 8.81 (s, 1H), 8.38 (t, J = 5.9 Hz, 1H), 7.96 (d, J =
8.2 Hz, 2H), 7.51 (d, J = 9.1 Hz, 1H), 7.46 (d, J = 8.2 Hz, 2H), 7.24 (dd, J =
9.1, 1.5 Hz, 1H), 4.57 (d, J = 7.2 Hz, 4H), 4.27 (t, J = 5.4 Hz, 2H), 3.80 (I, J = 5.4 Hz, 2H), 3.27 (d, J = 6.7 Hz, 4H), 2.98 (q, J = 7.5 Hz, 2H), 2.31 (s, 3H), 1.94 - 1.80 (m, 4H), 1.26 (t, J =
7.5 Hz, 3H).

Preparation of compound 51 Ca NI

= LNH 0 t N
0 I4s1-t,1 0*.1 .2 HCI 0 DIPEA, DCM
RT, 16 hours =
AE-5 compound 51 Accordingly, compound 51 was prepared in the same way as compound 47 starting from AE-5 (0.33 mmol) and N,N-Dimethylsulfamoyl chloride affording (0.69 mmol) yielding 0.07 g (40%).
1HNMR (400 MHz, DMSO) 8 8.81 (s, 1H), 8.40 (t, J = 6.0 Hz, 1H), 7.96 (d, J =
8.2 Hz, 2H), 7.51 (d, J = 9.1 Hz, 1H), 7.46 (d, J = 8.2 Hz, 2H), 7.24 (dd, J =
9.1, 1.6 Hz, 1H), 4.60 - 4.55 (m, 4H), 4.27 (t, J = 5.4 Hz, 2H), 3.81 (t, J = 5.4 Hz, 2H), 2.98 (q, J =
7.5 Hz, 2H), 2.83 (s, 6H), 2.31 (s, 3H), 1.26 (t, J = 7.5 Hz, 3H).
Synthesis of compound 55 Nok....,NH Br 0 11 OMe .2 HCI
DIPEA, ___________________________________ Isoamyl alcohol 130 C, 72 + 24 hours AE-5 compound 55 To a solution of AE-5 (0.15 g, 0.31 mmol) in Isoamyl alcohol (2 mL) was added DIPEA (0.16 g, 1.23 mmol) and 2-Bromoethyl methyl ether (0.032 mL, 0.34 mmol) at room temperature, the mixture was stirred at 130 C for 72 hours. Reaction mixture was recharged with DIPEA (1.5 eq.) and Isoamyl alcohol (0.5 mL) and stirred at 130 C for 24 h. The mixture was diluted with DCM and washed with saturated aqueous NaHCO3 solution. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography (SiOH;

DCM/Me0H (9/1) in DCM from 0/100 to 30/70). The desired fractions were collected and concentrated under vacuum. The product was triturated with DIPE to yield 0.037 g of compound 55 (25%) as a white solid.
NMR (400 MHz, DMSO) 6 8.80 (s, 1H), 8.40 (t, J = 6.0 Hz, 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 9.2 Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.25 (dd, J =
9.1, 1.7 Hz, 1H), 4.56 (d, J = 5.9 Hz, 2H), 4.16 (t, J = 5.4 Hz, 2H), 3.82 (s, 2H), 3.54 (t, J = 5.5 Hz, 2H), 3.27 (s, 3H), 3.05 (1, J = 5.5 Hz, 2H), 2.98 (q, J = 7.5 Hz, 2H), 2.78 (1, J = 5.5 Hz, 2H), 2.31 (s, 3H), 1.26 (t, J = 7.5 Hz, 3H) Synthesis of compound 56 Mel, DIPEA, DCM 0 RT, 16 hours 14tH
thi4411--2,eN
.2 HCI
AE-5 compound 56 Accordingly, compound 56 was prepared in the same way as compound 47 starting from AE-5 (0.31 mmol) and iodomethane (0.46 mmol) yielding 0.047 g (35%).
1HNMR (400 MHz, DMSO) d 8.80 (s, 1H), 8.40 (t, J = 5.6 Hz, 1H), 7.95 (d, J =
8.0 Hz, 2H), 7.51 (d, J = 9.1 Hz, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 9.0 Hz, 1H), 4.56 (d, J = 5.6 Hz, 2H), 4.17 (t, J = 5.1 Hz, 2H), 3.70 (s, 2H), 2.98 (q, J =
7.5 Hz, 2H), 2.92 (t, J = 5.3 Hz, 2H), 2.44 (s, 3H), 2.31 (s, 3H), 1.26 (t, J = 7.4 Hz, 3H).
Synthesis of compound 65 COOH HATU, DIPEA, 0 /-0-414;21,,,[44,CF3 r-\14 H2N =INN;11.,,,[44,CF3 DMF, RT, 18 h CAS [2059140-77-9] A-5 compound 65 Accordingly, compound 65 was prepared in the same way as compound 1 starting from 2-ethy1-7-methy1-6,8-dihydro-5H-imidazo[1,2-alpyrazine-3-carboxylic acid (CAS
[2059140-77-9], 0.66 mmol) and intermediate A-5 (0.44 mmol) affording 0.051 g (20%) as white solid.
1H NMR (400 MHz, DMSO-d6, 100 'V) 6 7.96 (d, J = 8.0 Hz, 2H), 7.87 (t, J = 5.3 Hz, 1H), 7.42 (d, J = 8.0 Hz, 2H), 4.93 (s, 2H), 4.50 (d, J = 5.9 Hz, 2H), 4.37 (t, J = 5.5 Hz, 2H), 4.16 (t, J = 5.4 Hz, 2H), 4.07 (t, J = 5.5 Hz, 2H), 3.53 (s, 2H), 2.76 (t, J = 5.5 Hz, 2H), 2.70 (q, J = 7.4 Hz, 2H), 2.39 (s, 3H), 1.15 (t, J = 7.5 Hz, 3H).

Synthesis of compound 66 BOC'N Bisipinacolato)thboron 134:0, Q
KOAc, Pd(dppf)CI,, Boc'N
B dioxane, 90 C, 16 V;.. B4O A-3 0 -117ZL Cs,CO, BOC

CAS [120157-97-3] C-1 Pd(dppf)C12 H20, dioxane, 100 C, 17 h COOH
HCI 4M in dioxane, HATU, DIPEA, DCM, at RT, 1611 B2N¨/-0-4NN:U40CF3 DMF, RT, 10 h .HCI N

A
N 0 eNN ..õ00 CF
compound 66 Preparation of intermediate C-1 To a N2 purged solution of tert-butyl N42-(4-bromophenyflethylicarbamate (CAS
[120157-97-31 0.9g. 3 mmol), Bis(pinacolato)diboron (1.14g. 4.5 mmol) and Potassium acetate (0.88 g, 8.9 mmol) in 1,4-dioxane (24 mL) was added [LF-Bis(diphenylphosphino)ferrocene] dichloropalladium(II) (245 mg, 0.3 mmol), then the reaction mixture was stirred at 90 C for 18 h. The reaction mixture was filtered on celitek, the filter cake was rinsed with Et0Ac and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel (Me0H in DCM 0/100 to 4/96) to afford intermediate C-1 as a beige solid, 0.7 g (64%).
Preparation of intermediate C-2 Al\I") purged mixture of intermediate C-1 (250 mg, 0.72 mmol), intermediate A-3 (219 mg, 0.65 nunol), Cesium carbonate (469 mg, 1.44 nunol) and 1,1'-Bis(diphenylphosphino) ferrocene dichloropalladium (II) (80 mg, 0.098 mmol) in 1,4-dioxane (4 mL) and water (1.8 mL) was stirred at 100 C for 17 h. The reaction mixture was cooled to rt, filtered on celite and the filter cake was washed with Et0Ac. The filtrate was concentrated and purified by flash chromatography over silica gel (Et0Ac in Heptane from 0/100 to 25/75) to afford intermediate C-2 as a white solid, 0.256 g (81%).

Preparation of intermediate C-3 To a nitrogen-purged mixture of C-2 (256 mg, 0.54 mmol) in dry DCM (10 mL) was added 4M solution of HC1 in 1,4-dioxane (0.81 mL, 3.23 mmol) at RT. The reaction mixture was stirred for 16 h. The reaction mixture was concentrated under reduced pressure to afford intermediate C-3 as a white solid, 0.216 g (89%).
Preparation of compound 66 Accordingly, compound 66 was prepared in the same way as compound 1 starting from intermediate AI-3 2-ethyl-6-methyl-imidazo[1,2-alpyrimidine-3-carboxylic acid (0.58 mmol) and intermediate C-3 (0.48 n-n-nol) yielding 0.171g (61%) as a white powder.
1H NMR (400 MHz, DMSO) d 8.99 (s, 1H), 8.48 (d, J = 2.2 Hz, 1H), 8.01 (t, J =
5.5 Hz, 1H), 7.93 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 4.96 (s, 2H), 4.36 (t, J = 5.3 Hz, 2H), 4.22 ¨ 4.08 (m, 2H), 3.61 (dd, J = 12.8, 6.6 Hz, 2H), 2.94 (t, J =
7.1 Hz, 2H), 2.83 (q, J = 7.5 Hz, 2H), 2.29 (s, 3H), 1.17 (t, J = 7.5 Hz, 3H).
Synthesis of compound 67 Br N ocE3NN
BOC' NI 13. 0 A-3 0 1r 7N CF3 "7cy_ Cs2CO3 Pd(dppf)Cl2 BOC

CAS [832114-05-3] H20, dioxane, 100 C, 16 h COOH
HCI 4M in dioxane, HATU, DIPEA, DMF, DCM RT, 18 h N (1:1 CF3 %S

.HCI

eip_of NN:LN,$),cF3 N N

compound 67 Preparation of intermediate C-4 Accordingly, intermediate C-4 was prepared in the same way as intermediate C-2 starting from tert-butylN4[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyllmethyllcarbamate (CAS [832114-05-3], 273 mg, 0.82 mmol), intermediate A-3 (250 mg, 0.75 mmol), affording intermediate C-4 as a white solid, 0.169 g (47%).
Preparation of intermediate C-5 Accordingly, intermediate C-5 was prepared in the same way as intermediate C-3 starting from intermediate C-4 (165 mg, 0.36 mmol) to afford intermediate C-5 as a white solid, 0.154 g (98%).
Preparation of compound 67 Accordingly, compound 67 was prepared in the same way as compound 1 starting from intermediate A1-3 2-ethy1-6-methyl-imidazo111,2-alpyrimidine-3-carboxylic acid (0.49 mmol) and intermediate C-5 (0.35 mmol) yielding 0.067g (34%) as a white powder.
1H NMR (4001V1Hz, DMSO) 5 9.14 (s, 1H), 8.58 (t, J = 5.8 Hz, 1H), 8.52 (s, 1H), 8.05 (s, 1H), 7.88 (d, J = 4.1 Hz, 1H), 7.51 ¨ 7.40 (m, 2H), 4.95 (s, 2H), 4.60 (d, J = 5.8 Hz, 2H), 4.36 (t, J = 5.1 Hz, 2H), 4.15 (s, 2H), 3.03 (q, J = 7.5 Hz, 2H), 2.34 (s, 3H), 1.28 (t, J = 7.4 Hz, 3H) Synthesis of compound 68 V Br¨to0 H N 00) CF
BOG ¨N F3 Aoc A-3 0 H II

Cs2CO3 Pd(dppf)Cl2 C-6 CAS [1313441-88-1] H20, dioxane, 100C, 8 h COOH
HAT, , HCI 4M in dioxane, .HCI 0 ' DCM, at RT, 16h NrAL....õNõ.11.,õCF3 =
DMF, UDIPEA
RT, 16 h 0 V' / 0 Nr.-N,gõc F3 N HN

corn pound 68 Preparation of intermediate C-6 Accordingly, intermediate C-6 was prepared in the same way as intermediate C-2 starting from tert-buty1N-[144-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)phenyl[cyclopropyl[carbamate (CAS [1313441-88-1], 483 mg, 1.35 mmol), intermediate A-3 (410 mg, 1.22 mmol), affording intermediate C-6 as a white solid, 0.337 g (56%).
Preparation of intermediate C-7 Accordingly, intermediate C-7 was prepared in the same way as intermediate C-3 starting from intermediate C-6 (322 mg, 0.66 mmol) to afford intermediate C-7 as a white solid, 0.331 g (99%).
Preparation of compound 68 Accordingly, compound 68 was prepared in the same way as compound 1 starting from intermediate A1-3 2-ethyl-6-methyl-imidazo[1,2-a]pyrimidine-3-carboxylic acid (0.41 mmol) and intermediate C-7 (0.32 mmol) yielding 0.170 g (92%) as a white powder 1H NMR (400 MHz, DMSO) 8 9.05 (dd, J = 2.3, 1.1 Hz, 1H), 8.76 (s, 1H), 8.51 (d, J
2.4 Hz, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 4.95 (s, 2H), 4.36 (t, J =
5.3 Hz, 2H), 4.20 ¨ 4.11 (m, 2H), 3.03 (q, J = 7.5 Hz, 2H), 2.33 (s, 3H), 1.38 (s, 4H), 1.28 (t, J = 7.5 Hz, 3H) Synthesis of compound 69 NiC126H20 N _ Br41:04LN.j...cF3 BOC20, NaB H4, A
Me0H
A-3 0 0 C to RT, 32h NH
Cs2CO3 NoL0,0õõC F3 A
CAS [1203798-71-3] Pd2(dba)3 xantphos dioxane, 100 C, 16 h BOC%N
101 HCI 4M in dioxane, H 2 N
DCM, at RT, 2h ¨tr.) 0 __________________________________________________________ N_P"-NeTh N+C F3 . HCI - F3 COOH
HATU, DIPEA, DMF, RT, 2 h hq.12.1 N _________________________________________________ 4 I H 101 NreLN
N¨C

1.0 compound 69 Preparation of intermediate C-8 A N2 purged mixture of 4-pyrrolidin-3-ylbenzonitrile (CAS [1203798-71-3], 155 mg, 0.9 mop, intermediate A-3 (250 mg, 0.75 mmol), Cesium carbonate (732 mg, 2.25 mmol), Tris(dibenzylideneacetone)dipalladium(0) (102 mg, 0.11 mmol) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (130 mg, 0.22 mmol) in 1,4-dioxane (7 mL) was stirred at 100 C for 16 h.
The reaction mixture was cooled down to RT, Ethyl acetate and NaHCO3 were added to the reaction mixture, the organic layer was separated, dried over MgSO4, filtered and concentrated under vacuum. The crude was purified by flash column chromatography (dry load in silica, Et0Ac in Heptane from 0/100 to 75/25) The desired fractions were collected and concentrated in vacuo to afford intermediate C-8 as a yellow oil, 0.145 g (40%).
Preparation of intermediate C-9 To a nitrogen-purged mixture of intermediate C-8 (145 mg, 0.32 mmol), Nickel(II) chloride hexahydrate (58 mg, 0.24 mmol), Di-tertbutyl dicarbonate (211 mg, 0.97) in dry Me0H (3 mL) was added portionwise Sodium borohydride (73 mg, 1.94), mmol) at 0 C. The reaction mixture was stirred at RT for 32 h. A solution of NH4C1 sat.
aqueous was added and the mixture was extracted with DCM (x3). The organic layer was dried with MgSO4, filtrated, and concentrated in yacuo to yield intermediate C-9 as a brown solid, 0.092 g (43%) that it was used in the next step without further purification.
Preparation of intermediate C-10 Accordingly, intermediate C-10 was prepared in the same way as intermediate C-starting from intermediate C-9 (92 mg, 0.17 mmol) to afford intermediate C-10 as a purple solid, 0.080 g (79%).
Preparation of compound 69 Accordingly, compound 69 was prepared in the same way as compound 1 starting from intermediate AI-3 2-ethyl-6-methyl-imidazo11,2-alpyrimidine-3-carboxylic acid (0.21 mmol) and intermediate C-10 (0.16 mmol) yielding 40 mg (39%) as a white powder.
1H NMR (400 MHz, DMSO-d6, 25 C) 5 9.24 - 9.20 (m, 1H), 8.73 - 8.65 (m, 2H), 7.33 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 4.75 (s, 2H), 4.52 (d, J =
5.8 Hz, 2H), 4.07 (s, 4H), 3.76 (dd, J = 9.5, 7.5 Hz, 1H), 3.64 -3.51 (m, 4H), 3.03 (q, J =
7.5 Hz, 2H), 2.39 (s, 3H), 1.98 (dq, J = 12.1, 8.4 Hz, 2H), 1.29 (t, J = 7.5 Hz, 3H).
1H NMR (400 MHz, DMSO-d6, 100 C) 5 9.16 (dd, J = 2.3, 1.1 Hz, 1H), 8.54 (d, J
=
2.4 Hz, 1H), 8.15 (s, 1H), 7.35 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H), 4.73 (s, 2H), 4.55 (d, J = 5.8 Hz, 2H), 4.08 (dq, J = 8.2, 4.2 Hz, 4H), 3.79 (dd, J =
9.6, 7.5 Hz, 1H), 3.58 - 3.40 (m, 3H), 3.36 - 3.27 (m, 1H), 2.38 - 2.35 (m, 3H), 2.07 -1.95 (m, 2H), 1.31 (t, J = 7.5 Hz, 3H). CH2 missed, CH2 inside of water signal.

Synthesis of compound 70 NiC126H20 BrJ1 0 BOC20, NaBH4, II
#=¨µ N.,"\i N= = N N_e õc F3 Me0H
0 C to RT, 16h H Cs2CO2 ii Pd2(dba)2 CAS [68104-63-2] xantphos toluene 100 C, 16 h N 0 HCI 4M in dioxane, N N_e BOC ¨N \/, N,g 0,C F3 DCM, at RT, 2h H N \¨/
H II .HCI

COOH

HATU, DIPEA, ?=\
DMF, RT, 2 h \
II
H
N¨µ ]
Al-3 compound 70 Preparation of intermediate C-11 Accordingly, intermediate C-11 was prepared in the same way as intermediate C-starting from intermediate 4-piperazin-1 -y lbenzonitrile (CAS [68104-63-2], 200 mg, 0.89 mmol),), intermediate A-3 (250 mg, 0.75 mmol), in Toluene (20 mL) to afford intermediate C-11 as a yellow solid, 0.134 g (39%).
Preparation of intermediate C-12 Accordingly, intermediate C-12 was prepared in the same way as intermediate C-starting from intermediate C-11 (364 mg, 0.82 mmol) to afford intermediate C-12 as a yellow solid, 0.450 g (90%).
Preparation of intermediate C-13 Accordingly, intermediate C-13 was prepared in the same way as intermediate C-starting from intermediate C-12 (449 mg, 0.74 mmol) to afford intermediate C-13 as a yellow solid, 0.384 g (85%).

Preparation of compound 70 Accordingly, compound 70 was prepared in the same way as compound 1 starting from intermediate A1-3 2-ethy1-6-methy1-imidazo[1,2-alpyrimidine-3-carboxylic acid (0.82 mmol) and intermediate C-13 (0.63 mmol) yielding 136 mg (34%) as a beige solid.
1H NMR (400 MHz, DMSO) 5 9.12 (s, 1H), 8.50 (d, J = 2.3 Hz, 1H), 8.40 (t, J =
5.9 Hz, 1H), 7.25 (d, J = 8.5 Hz, 2H), 6.97 (d, J = 8.6 Hz, 2H), 4.77 (s, 2H), 4.43 (d, J = 5.8 Hz, 2H), 4.09 (dd, J = 12.8, 4.3 Hz, 4H), 3.47 ¨3.40 (m, 4H), 3.22 ¨ 3.13 (m, 4H), 2.98 (q, J = 7.5 Hz, 2H), 2.33 (s, 3H), 1.26 (t, J = 7.5 Hz, 3H).
Synthesis of compound 71 Nici,61120 mB0e0C2H0, NaBH4, Br¨emoNai cF3 Ner...L+CF3 A-3 N=
1 Br 0 C to RT, 16h e 0 Cul, DMF
CAS [117269-72-4] C-14 Pd(dppf)Cl2 90 C, 16 h y-N-Th BOC¨N NOL....=NijeCF3 HCI 4M in dioxane. H2N
11 DCM, at RT, 1h II

.HCI

HATU, DIPEA, N N

DMF, RT, 2 h N
compound 71 Preparation of intermediate C-14 111,1'-13is(diphenylphosphino)ferroceneldichloropalladium (II) complex with dichloromethane_ylbenzonitrile (CAS [95464-05-4], 49 mg, 0.06 mmol) and CuI
(11 mg, 12 mmol) were added to a stirred solution of intermediate A-3 (200 mg, 0.6 mmol) in DMF (9 mL) in a round bottom flask 2-neck equiped with a condenser at rt while nitrogen was bubbling. Then, (3-CyanobenzyDzinc bromide (CAS [117269-72-4], mg, 2.39 mmol, 0.24 M solution in THF) was added via srynge to the stirred suspension under nitrogen. The mixture was stirred at 90 C for 16 h. The mixture was diluted with water and extracted with AcOEt. The organic layer was separated, dried (MgSO4), filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; Ethyl acetate in heptane 0/100 to 100/0). The desired fractions were collected and concentrated in vacuo to yield intermediate C-14 as a brown solid 0.080 g (36%).
Preparation of intermediate C-15 Accordingly, intermediate C-15 was prepared in the same way as intermediate C-starting from intermediate C-14 (80 mg, 0.22 mmol) to afford intermediate C-15 as a brown oil, 0.095 g (83%).
Preparation of intermediate C-16 Accordingly, intermediate C-16 was prepared in the same way as intermediate C-starting from intermediate C-15 (80 mg, 0.2 mmol) to afford intermediate C-16 as a yellow solid, 0.090 g (90%).
Preparation of compound 71 Accordingly, compound 71 was prepared in the same way as compound 1 starting from intermediate AI-3 2-ethy1-6-methyl-imidazo[1,2-alpyrimidine-3-carboxylic acid (0.24 mmol) and intermediate C-16 (0.2 mmol) yielding 55 mg (47%) as a brown solid.
1H NMR (400 MHz, DMSO) 5 9.13 (s, 1H), 8.55 ¨ 8.43 (m, 2H), 7.35 ¨ 7.10 (m, 4H), 4.81 (s, 2H), 4.50 (d, J = 5.0 Hz, 2H), 4.22(s, 2H), 4.16 ¨ 4.01 (m, 4H), 3.04 ¨ 2.94 (m, 2H), 2.33 (s, 3H), 1.26 (t, J = 7.3 Hz, 3H).

Synthesis of compound 72 NiC126H20 Br¨e0.0 0 C BOC20, NaBH4, N CF3 0 C to RT, 16h Me0H, dioxane I A-3 0 ""=:._s0 II
Pd(PPh3)4 CAS [1240608-82-5] Sn2(CH3)6 C-17 Toluene, 110 C, 37 h BOC HCI 4M in dioxane, NeNsleTh 0 I Nfs4 I IN,cF3 _________ 0 DCM, at RT, 16h ,g,cF3 o =...q .HCI II
II
0 N-Avo=N

COOH
HATU, DIPEA, 0 DMF, RT, 2 h N
_____________________________________ 3.= N.-4 I 1 0 0 N.==== N
+CF3 II

compound 72 Preparation of intermediate C-17 Tetrakis(triphenylphosphine)palladium(0) (CAS [14221-01-3]. 334 mg, 0.29 mmol) was added under N2 atmosphere to a mixture of intermediate A3 (484 mg, 1.45 mmol), Hexamethylditin (CAS [661-69-8], 0.3 mL, 1.45 mmol, 1.58 gimL) in toluene (20 mL).The mixture was stirred at 110 C, for 5 h. Then, 2-bromooxazole-4-carbonitrile (CAS [1240608-82-5], 375 mg, 2.17 mmol) and additional Tetrakis(triphenylphosphine)palladium(0) (CAS [14221-01-3], 334 mg, 0.29 mmol) were added to the reaction mixture and stirred at 110 C for additional 16 h.
Reaction incomplete, Tetrakis(triphenylphosphine)palladium(0) (CAS [14221-01-3], 334 mg, 0.29 mmol) was added at rt and the mixture was stirred at 110 C for 16h. The mixture was cooled down at rt and filtered through of pad of celite. Solvent was concentrated in vacuo. The reaction crude was purified by flash column chromatography (silica gel, Et0Ac in heptane from 0/100 to 100/0). The desired fractions were combined, and the solvent removed in vacuo to yield intermediate C-17 as a yellow solid 362 mg (50%).

Preparation of intermediate C-18 Accordingly, intermediate C-18 was prepared in the same way as intermediate C-starting from intermediate C-17 (316 mg, 0.91 mmol) to afford intermediate C-18 as a brown oil, 0.434 g (95%).
Preparation of intermediate C-19 Accordingly, intermediate C-19 was prepared in the same way as intermediate C-starting from intermediate C-18 (434 mg, 0.58 mmol) to afford intermediate C-19 as a yellow solid, 0.372 g (100%).
Preparation of compound 72 Accordingly, compound 72 was prepared in the same way as compound 1 starting from intermediate AI-3 2-ethyl-6-methyl-imidazo[1,2-a]pyrimidine-3-carboxylic acid (0.75 mmol) and intermediate C-19 (0.58 mmol) yielding 55 mg (18%) as a beige solid.
1H NMR (400 MHz, DMSO) d 9.16 (s, 1H), 8.51 (d, J = 2.4 Hz, 1H), 8.46 (t, J =
5.7 Hz, 1H), 8.17 (s, 1H), 4.98 (s, 2H), 4.50 (d, J = 5.6 Hz, 2H), 4.41 (t, J =
5.4 Hz, 2H), 4.22 ¨ 4.11 (m, 2H), 3.00 (q, J = 7.5 Hz, 2H), 2.35 (s, 3H), 1.27 (t, J = 7.5 Hz, 3H).
Synthesis of compound 73 Br¨en 'BocN.. N. N HCI 4M in dioxane, N
)¨Br CAS [1575613-02-3] I .1)¨e DCM, at RT, 16h .-N/\.õ
s -*====="...."130C _____ S
H
Pd(PPI94 CAS [848501-90-6] Sn2(CH3)4 C-20 Toluene, 100 C, 60 h NiC126F120 BOC20, NaBH4, (CF3902)20, DIPEA
Me0H, dioxane DCM, 0 C to RT, 1h 0 C to RT, 48h S
ii""CF3 COOH
HCI 4M in dioxane, H2 N HATU, DIPEA, 41/1.-1:se DMF, DCM, at RT, 16h S
.HCI iCCF3 =µNN41.3try i%CF3 compound 73 Preparation of intermediate C-20 Accordingly, intermediate C-20 was prepared in the same way as intermediate C-

17 starting from 2-bromothiazole-4-carbonitrile (CAS [848501-90-6], 280 mg, 1.48 mmol), and tert-butyl 2-bromo-6,8-dihydro-5H-[1,2,41triazolo[1,5-a]pyrazine-7-carboxylate (CAS [1575613-02-3], 300 mg, 0.99 mmol), to afford intermediate C-20 as a pale yellow solid, 0.165 g (50%).
Preparation of intermediate C-21 Accordingly, intermediate C-21 was prepared in the same way as intermediate C-starting from intermediate C-20 (165 mg, 0.5 mmol) to afford intermediate C-21 as a white solid, 0.145 g (100%).
Preparation of intermediate C-22 Trifluoromethanesulfonic anhydride (CAS [358-23-6], 0.100 mL, 0.59 mmol), was added dropwise to a stirred solution of intermediate C-21 (145 mg, 0.54 mmol), DIPEA
(0.282 mL, 1.60 mmol) in DCM (6 mL) in a round bottom flask under N2 atmosphere at 0 C. The mixture was stirred for 30 mm at 0 C and 1 h at rt. Aqueous saturated NaHCO3 solution was added and the mixture was extracted with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica; ethyl acetate in heptane from 0/100 to 30/70). The desired fractions were collected and concentrated in vacuo to yield intermediate C-22 as a white solid 0.077 g (39%).

Preparation of intermediate C-23 Accordingly, intermediate C-23 was prepared in the same way as intermediate C-starting from intermediate C-22 (75 mg, 0.21 mmol) to afford intermediate C-23 as a brown solid, 83 mg (86%).
Preparation of intermediate C-24 Accordingly, intermediate C-24 was prepared in the same way as intermediate C-starting from intermediate C-23 (83 mg, 0.18 mmol) to afford intermediate C-24 as a yellow solid, 87 mg (99%).
Preparation of compound 73 Accordingly, compound 73 was prepared in the same way as compound 1 starting from intermediate AI-3 2-ethyl-6-methyl-imidazo[1,2-a]pyrimidine-3-carboxylic acid (0.19 mmol) and intermediate C-24 (0.18 mmol) yielding 15 mg (10%) as a yellow solid.
1H NMR (400 MHz, DMSO) d 9.18 ¨ 9.15 (m, 1H), 8.57 (t, J = 5.9 Hz, 1H), 8.51 (d, J
= 2.4 Hz, 1H), 7.62 (s, 1H), 4.98 (s, 2H), 4.69 (d, J = 5.8 Hz, 2H), 4.39 (t, J = 5.4 Hz, 2H), 4.17 (t, J = 5.1 Hz, 2H), 3.02 (q, J = 7.5 Hz, 2H), 2.34 (s, 3H), 1.28 (t, J = 7.5 Hz, 3H).

Synthesis of compound 74 NiCI261-120 N.0,, 0 BOC20, NaBH4, j)¨Br A-3 ...CN1"--le..%1N 0 Me0H BOC
0 C to RT, 91h I ,CF3 ,R,CF3 N 14 1=,, Pd(PPII),, CAS [440100-94-7] Sn2(CH3)6 C-25 C-Toluene, 100 C, 30 h COOH
HCI 4M M dioxane, .HCI HATU, DIPEA, DCM, at RT, 2h DMF, RT, 2 h N N NsII,CF3 Isr 4-N

CF

compound 74 Preparation of intermediate C-25 Accordingly, intermediate C-25 was prepared in the same way as intermediate C-starting from 2-bromothiazole-5-carbonitrile (CAS [440100-94-71, 500 mg, 2.54 mmol), and intermediate A3 (567 mg, 1.69 mmol), to afford intermediate C-25 as a pale brown solid, 0.180 g (26%).
Preparation of intermediate C-26 Accordingly, intermediate C-26 was prepared in the same way as intermediate C-starting from intermediate C-25 (233 mg, 0.64 mmol) to afford intermediate C-26 as a brown oil, 0.299 g (85%).
Preparation of intermediate C-27 Accordingly, intermediate C-27 was prepared in the same way as intermediate C-starting from intermediate C-26 (299 mg, 0.54 mmol) to afford intermediate C-27 as a yellow solid, 0.280 g (58%).

Preparation of compound 74 Accordingly, compound 74 was prepared in the same way as compound 1 starting from intermediate AI-3 2-ethy1-6-methy1-imidazo[1,2-alpyrimidine-3-carboxylic acid (0.38 mmol) and intermediate C-27 (0.32 mmol) yielding 38 mg (21%) as a brown solid.
1H NMR (400 MHz, DMSO) 6 9.19 (dd, J = 2.3, 1.1 Hz, 1H), 8.61 (t, J = 5.8 Hz, 1H), 8.53 (d, J = 2.4 Hz, 1H), 7.89 (s, 1H), 4.97 (s, 2H), 4.75 (d, J = 5.7 Hz, 2H), 4.39 (t, J
5.4 Hz, 2H), 4.16 (d, J = 5.1 Hz, 2H), 2.99 (q, J = 7.5 Hz, 2H), 2.35 (s, 3H), 1.26 (1, J
7.5 Hz, 3H).
Synthesis of compound 75 Br4-0 CF3 BOC
N BOC HCI
4M in dioxane, 'Ist".The?)¨Br A-3 DCM, at RT, 2h H S _________________________________ 1.= kCF3 _________ Pd(PPh3)4 0 CAS [697299-87-9] Sn2(C1-13)6 C-28 Toluene, 100 C, 30 h COOH HATU, DIPEA, N--N

._, 0 .CNL/ DMF, RT, 2 h s, 1 .HCI N

AI-3 compound Preparation of intermediate C-28 Accordingly, intermediate C-28 was prepared in the same way as intermediate C-starting from tert-butyl N-[(4-bromothiazol-2-yOmethyllcarbamate (CAS [697299-9], 750 mg, 2.56 mmol), and intermediate A3 (571 mg, 1 71 mmol), to afford intermediate C-28 as a yellow oil, 0.403 g (29%).
Preparation of intermediate C-29 Accordingly, intermediate C-29 was prepared in the same way as intermediate C-starting from intermediate C-28 (403 mg, 0.49 mmol) to afford intermediate C-29 as a yellow solid, 0.360 g (100%).

Preparation of compound 75 Accordingly, compound 75 was prepared in the same way as compound 1 starting from intermediate A1-3 2-ethy1-6-methy1-imidazo[1,2-alpyrimidine-3-carboxylic acid (0.69 mmol) and intermediate C-29 (0.49 mmol) yielding 32 mg (12%) as a beige solid.
1H NMR (400 MHz, DMSO) d 9.19 (s, 1H), 8.84 (t, J = 5.9 Hz, 1H), 8.54 (d, J =
2.4 Hz, 1H), 8.06 (s, 1H), 4.95 (s, 2H), 4.86 (d, J = 5.9 Hz, 2H), 4.36 (t, J =
5.4 Hz, 2H), 4.17 (t, J = 5.3 Hz, 2H), 3.07 (q, J = 7.5 Hz, 2H), 2.35 (s, 3H), 1.32 (t, J =
7.5 Hz, 3H).
Synthesis of compound 76 COOH HATU, DIPEA, 0 DMF, RT, 2 h =frS
_____________________________________________________________ , .HCI _Br CAS [1823928-17-1] C-30 Al-3 Br N n CF
_______________________________ 31.= N¨( N"-N N's' 3 Pd(PPh3)4 Sn2(CH3)6 Toluene, compound 76 100 C, 30 h Preparation of intermediate C-30 Accordingly, intermediate C-30 was prepared in the same way as compound 1 starting from intermediate A1-3 2-ethyl-6-methyl-imidazo[1,2-a]pyrimidine-3-carboxylic acid (158 mg 0.77 mmol) and (5-bromo-1,3,4-thiadiazol-2-yOmethanamine hydrochloride (CAS [1823928-17-U 187 mg 0.7 mmol) yielding 260 mg (68%) as a brown solid.

Preparation of compound 76 Accordingly, compound 76 was prepared in the same way as intermediate C-17 starting from intermediate C-30 (180 mg, 0.33 mmol), and intermediate A3 (221 mg, 0.66 mmol), yielding 38 mg (20%) as a beige solid.
1H NMR (400 MHz, DMSO) 6 9.22 (s, 1H), 8.85 (s, 1H), 8.61 ¨ 8.47 (m, 1H), 5.00 (s, 2H), 4.97 (s, 2H), 4.43 (t, J = 5.4 Hz, 2H), 4.17 (mõ 2H), 3.04 (q, J = 7.5 Hz, 2H), 2.35 (s, 3H), 1.29 (t, J = 7.5 Hz, 3H).
Synthesis of compound 77 NiC126H20 N
NNõ. 41Ø-L,N,(8),cF, _N N
BOC20, NaBH4, Me0H, dioxane A-3 0 CF 0 C to RT, 72h Pd(PP1.13)4 Sn2(CH3)6 CAS [1020253-14-8] C-31 Toluene, 110 C, 152 h HC1 4M in dioxane, BOC¨N NrOL,N CF DCM, at RT, 16h 0 .HC1 0 C

COOH
CI HATU, DIPEA, CI 0 o DMF, RT, 2 h hõ, N
H
N N
CAS [2059140-68-8]
compound 77 Preparation of intermediate C-31 Accordingly, intermediate C-31 was prepared in the same way as intermediate C-starting from 6-chloro-5-fluoro-pyridine-3-carbonitrile (CAS [1020253-14-8], 1 g, 6.39 mmol), and intermediate A3 (713 mg, 2.13 mmol), to afford intermediate C-31 as a yellow oil, 0.234 g (12%).

Preparation of intermediate C-32 Accordingly, intermediate C-32 was prepared in the same way as intermediate C-starting from intermediate C-31 (257 mg, 0.68 mmol) to afford intermediate C-32 as a brown solid 0.276 g (54%).
Preparation of intermediate C-33 Accordingly, intermediate C-33 was prepared in the same way as intermediate C-starting from intermediate C-32 (275 mg, 0.57 mmol) to afford intermediate C-33 as a yellow solid, 0.285 g (99%).
Preparation of compound 77 Accordingly, compound 77 was prepared in the same way as compound 1 starting from 6-chloro-2-ethyl-imidazo[1,2-a]pyrimidine-3-carboxylic acid (CAS [2059140-68-8], 0.74 mmol) and intermediate C-33 (0.57 mmol) yielding 38 mg (12%) as a brown solid.
1H NMR (400 MHz, DMSO) 6 9.44 (d, J = 2.6 Hz, 1H), 8.69 (d, J = 2.6 Hz, 1H), 8.64 (t, J = 6.0 Hz, 1H), 8.58 (s, 1H), 7.87 (d, J = 10.9 Hz, 1H), 4.99 (s, 2H), 4.66 (d, J = 5.6 Hz, 2H), 4.42 (t, J = 5.3 Hz, 2H), 4.18 (s, 2H), 3.06 (q, J = 7.5 Hz, 2H), 1.30 (t, J = 7.5 Hz, 3H).

Synthesis of compound 78 I
0 r-,0 A.... 0 :
\
0 0 0 or¨

IP
.....t)_/
Girt...L...
I CAS [4949-44-4] ..r...11....rti CAS
[20781-20-8]
-.N * ''''' N

34 C- .... ..:N1 .t_ CAS [1260667-65-9] KHCO, I
BrCCI, CU/

CAS [29046-78-4]
90 C, 16 h (Ir[dF(CF3)ppy]2(dtbpy))PF6 CAS [870987-63-6]
DABCO, DMA
blue light LED, rt 32 h BOG20, Et3N, 0 r=-= 0 .....ti_0_1/1 .0 DMAP, DCM, LIOH, CI
+ H2N"¨c N N
..
,..
dioxane "' CF
a ' Et0H, Wate r 0 Nret ¨Q¨i-1....,N 9 I to 50 C, 54h 50 C 2 h N
S' 3 ____________________ I. *
0 CNItkli,--I

_______________________________________________ t 41) OC .HCI F

HATU, DIPEA, 0 \ i oxl.,......,N (13 CF TFA
II
DMF, RT, 2 h .....Vcc)¨(N I, 16h F

Cl r.,....L h compound 78 le 6oc o Preparation of intermediate C-34 Ethyl propionylacetate (CAS [4949-44-4], 0.100 mL, 0.59 mmol), was added to a stirred mixture of 5-Chloro-4-iodopyridin-2-amine (CAS [1260667-65-91, 3.6 g, 14.15 mmol), KHCO3 ( 3.1 g, 31.13 mmol), Bromotrichloromethane (CAS [75-62-7], 5.5 g, 56.59 mmol), in Acetonitrile (10 mL) at rt. The mixture was stirred at 90 C
for 16 hours. Then, the mixture was diluted with Et0Ac and washed with sat. NaHCO3 aq.
solution. The organic layer was separated, dried over MgSO4, filtered, and concentrated in vacuo. The crude was purified by flash column chromatography (silica;
Et0Ac/Heptane from 0/100 to 25/75). The desired fractions were collected, and the solvent evaporated in vacuo to yield intermediate C-34 1.13 g, (20%) as a yellow powder.
Preparation of intermediate C-35 In a screw top vial, a solution of Nickel(II) chloride ethylene glycol dimethyl ether complex (CAS [29046-78-4], 105 mg, 0.48 mmol), in DMA (1mL) was added to a mixture of intermediate C-34, 2,4-Dimethoxybenzylamine (0.7 mL), (I4dF(CF3)ppy12.(dtbpy))PF6 (CAS [870987-63-6], 54 mg, 0.44 mmol), in DMA
(8mL) under nitrogen at rt. The mixture was degassed with nitrogen, the vial was closed, and the mixture stirred at rt and irradiated with blue light LED for 32 h. The mixture was diluted with saturated NaHCO3 aqueous solution and extracted with AcOEt. The organic layer was dried over MgSO4, filtered and concentrated in vacuo.
The crude product was purified by flash column chromatography (silica AcOEt/heptane from 0/100 to 70/30). The desired fractions were collected, and the solvent evaporated in vacuo to yield intermediate C-35 0.250 g, (24%) as a yellow solid.
Preparation of intermediate C-36 In a round bottom flask, Di-tertbutyl decarbonate (0.5 g, 2.34 mmol) was added to a solution of intermediate C-35 (0.245 g, 0.59 mmol), Triethylamine (0.6 mL, 4.39 mmol), and DMAP (3.58 mg, 0.029 mmol), in DCM (2 mL) at rt. The mixture was stirred at rt for 16h. The reaction mixture was concentrated in vacuo and dioxane was added (2 mL). The reaction mixture was stirred at 100 C for 16h.
The reaction mixture was diluted with water and brine solution and extracted with DCM. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, AcOEt in DCM from 0/100 to 40/60)). The desired fractions were collected and concentrated in vacuo to yield intermediate C-36, 0.270 g, (88%) as a beige solid.
Preparation of intermediate C-37 To a solution of intermediate C-36 (270 mg, 0.52 mmol) in water (2.5 mL) and Et0H
(9 mL) was added LiOH (66 mg, 1.56 mmol). The reaction mixture was stirred for 2 h at 50 C. Then HC1 1 M aq. solution was added until pH 7, and the solvent was evaporated in vacuo to yield intermediate C-37, 0.280 g, (100%) as an orange solid.
The reaction mixture was used in the next step without any further purification.

Preparation of intermediate C-38 Accordingly, intermediate C-38 was prepared in the same way as compound 1 starting from intermediate C-37 (277 mg, 0.52 mmol) and intermediate C-33 (472 mg, 1.04 mmol) yielding 113 mg (12%) as a yellow foam.
Preparation of compound 78 TFA (1.13 mL) was added to intermediate C-38 (100 mg, 0.12 mmol) at 0 C.The mixture was stirred at rt for 16 h. The mixture was neutralized with sat.
aqueous NaHCO3 solution and extracted with DCM. The organic layer was separated. dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude was purified by flash column chromatography (silica; DCM/Me0H (9:1) in DCM from 0/100 to 60/40).
The desired fractions were collected, and the solvent was evaporated in vacuo.
Diethylether and pentane were added and dried under vacuo to yield compound 78, 26 mg (37%) as a white solid.
1H NMR (400 MHz, DMSO) d 9.05 (s, 1H), 8.55 (s, 1H), 8.08 (t, J = 5.9 Hz, 1H), 7.81 (d, J = 11.4 Hz, 1H), 6.64 (s, 1H), 6.13 (s, 2H), 4.99 (s, 2H), 4.60 (d, J =
5.8 Hz, 2H), 4.42 (1, J = 5.4 Hz, 2H), 4.18 (1, J = 5.1 Hz, 2H), 3.00 ¨ 2.84 (m, 2H), 1.24 (1, J = 7.5 Hz, 3H).
Synthesis of compound 79 and 80 BOC¨Nt8s0 Pd(dppf)C12 Tf20 1M in DCM, Hp, dioxane, Et,N, dry DCM, = / Br ¨(1":0 N-- NH 0 C to RT, 16h Br _ix-) N__ Ns.g...CF3 90 C, 16 h _________________________________________________________________ BOC¨N
Nh14.CF3 C-39 (3 Y=H, CAS [330794-35-9]
Y=H, C-40 CAS [1523006-94-1] Y=F, B-3 Y=F, C-41 COOH

DCM, 0 HCI 4M into dioxane, H2N CF3 * leTh HATU, DIPEA, DMF, RT, 18 h Ntiv C RT, 16h .HCI Y=H, C-42 Y=F, C-43 X=C, CAS [1216036-36-0]
X=C, Y=H, compound 79 X=N, AI-3 X=N, Y=F, compound 80 Preparation of intermediate C-39 Accordingly, intermediate C-39 was prepared in the same way as intermediate A-starting from intermediate 2-bromo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (CAS
[1523006-94-1], 823 mg, 4.07 mmol), to afford intermediate C-39 as a yellow solid, 0.606 g (44%).
Preparation of intermediate C-40 Accordingly, intermediate C-40 was prepared in the same way as intermediate C-starting from intermediate C-39 (1.87 mmol) and tert-butylN4[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny11methylicarbamate (CAS [330794-35-9], 2.62 mmol) affording 0.607 g (63%) as yellow solid.
Preparation of intermediate C-41 Accordingly, intermediate C-41 was prepared in the same way as intermediate C-starting from intermediate C-39 (0.37 mmol) and intermediate B-3 (0.52 mmol) affording 133 mg (74%) as beige solid.
Preparation of intermediate C-42 Accordingly, intermediate C-42 was prepared in the same way as intermediate C-starting from intermediate C-40 (607 mg, 1.32 mmol) to afford intermediate C-42 as a white solid. 0.580 g (91%).
Preparation of intermediate C-43 Accordingly, intermediate C-43 was prepared in the same way as intermediate C-starting from intermediate C-41 (133 mg, 0.28 mmol) to afford intermediate C-43 as a white solid_ 0.116 g (99%).
Preparation of compound 79 Accordingly, compound 79 was prepared in the same way as compound 1 starting from 2-ethy1-6-methyl-imidazo[1,2-alpyridine-3-carboxylic acid (CAS [1216036-36-0], 0.42 mmol) and intermediate C-42 (0.3 mmol) yielding 0.050g (29%) as a yellow powder.

1H NMR (400 MHz, DMSO) 8 8.79 (s, 1H), 8.37 (t, J = 5.8 Hz, 1H), 7.71 (d, J =
8.0 Hz, 2H), 7.67 (s, 1H), 7.51 (d, J = 9.1 Hz, 1H), 7.35 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 9.1 Hz, 1H), 4.79 (s, 2H), 4.52 (d, J = 5.9 Hz, 2H), 4.17 (t, J = 5.3 Hz, 2H), 4.04 (t, J = 7.1 Hz, 2H), 2.97 (q, J = 7.5 Hz, 2H), 2.31 (s, 3H), 1.25 (t, J = 7.5 Hz, 3H) Preparation of compound 80 Accordingly, compound 80 was prepared in the same way as compound 1 starting from intermediate AI-3 (0.44 mmol) and intermediate C-43 (0.28 mmol) yielding 0.043g (27%) as a brown solid.
1H NMR (400 MHz, DMSO) 5 9.09 (s, 1H), 8.45 (d, J = 2.4 Hz, 1H), 8.41 (t, J =
6.0 Hz, 1H), 7.90 (t, J = 8.1 Hz, 1H), 7.51 (d, J = 41 Hz, 1H), 7.19 (s, 1H), 7.16 (d, J = 3.9 Hz, 1H), 4.75 (s, 2H), 4.48 (d, J = 5.9 Hz, 2H), 4.13 (t, J = 5.4 Hz, 2H), 4.03 ¨3.96 (m, 2H), 2.96 (q, J = 7.5 Hz, 2H), 2.27 (s, 3H), 1.22 (t, J = 7.5 Hz, 3H).
Synthesis of compound 81 COON
''t114:4_2 CAS [1216036-36-0]
HATU, DIPEA, 0 'Os' CF
N 2 CF DMF, , 3 RT18 h N II 0 AG-4 compound Preparation of compound 81 Accordingly, compound 81 was prepared in the same way as compound 1 starting from intermediate AG-4 (0.35 mmol) and 2-ethy1-6-methyl-imidazo[1,2-a]pyridine-3-carboxylic acid (CAS [1216036-36-0], 0.53 mmol) yielding 0.034g (18%) as a white foam.
1H NMR (400 MHz, DMSO) 5 8.80 (s, 1H), 8.39 (t, J = 5.9 Hz, 1H), 7.75 (d, J =
8.1 Hz, 2H), 7.51 (d, J = 9.1 Hz, 1H), 7.41 (d, J = 8.1 Hz, 2H), 7.24 (dd, J =
9.1, 1.3 Hz, 1H), 6.63 (s, 1H), 4.87 (s, 2H), 4.54 (d, J = 5.9 Hz, 2H), 4.28 (t, J = 5.5 Hz, 2H), 4.10 (t, J = 4.9 Hz, 2H), 2.98 (q, J = 7.5 Hz, 2H), 2.31 (s, 3H), 1.26 (t, J = 7.5 Hz, 31-1).

Synthesis of compound 82 Bis(pmacolato)chboron DMAP, DIPEA, sr KOAc, Pd(dppf)C12dioxa 16 h CbZ-N, DCM, 0 C- RT, 16 h B!)-t Br _______________________________ CbZ-N 0 CAS [1214342-53-6]
Cs2CO3, Pd(dppf)Cl2 HCI 4M in diozana, H20, diozane, --reTh DCM, 0 C to RT, 16h NH
90 C, 16 h = 1 _____________________________________ Cbz-N N'BOC ________ Cbz-N
'BOC

.HCI
CAS [1823835-34-2]
Tf20 1M in DCM, Pd(OH)2, Hz Et,N, dry DCM; Et0C, Me0H, 0 C to RT, 18h 0 RT, 90 min c _____________________________________ Cbz-N Ns.g..CF3 H 2N
N41,, F3 H II II

COOH

HATU, DIPEA,II
N,g,,CF3 DMF, RT, 18 h Nrril compound 82 Preparation of intermediate C-44 DMAP (CAS [1122-58-3], 25 mg, 0.21 mmol) and DIPEA (CAS [7087-68-5], 1.45 mL, 8.32 mmol) were added to a stirred solution of (4-Bromo-3-fluorophenyl) methanamine hydrochloride (CAS [1214342-53-6], 500 mg, 2.08 mmol) in DCM (21 mL) in a round bottom flask at 0 C. Then Benzyl chloroformate (CAS [501-53-1], 0.45 mL, 3.12 mmol, 1.2 g/mL) was added dropwise at 0 C. The mixture was stirred at rt for 16 h. The mixture was diluted with DCM and aqueous saturated NaHCO3 solution was added. The organic layer was separated, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified flash column chromatography (silica, Et0Ac in Heptane (0/100 to 20/80)). The desired fractions were collected and concentrated in vacuo to yield intermediate C-44, as a white solid, 625 mg (77%).
Preparation of intermediate C-45 Accordingly, intermediate C-45 was prepared in the same way as intermediate C-starting from intermediate C-44 (1.6 g, 4.73 mmol), affording intermediate C-45 as a Yellow solid, 1.6 g (82%).

Preparation of intermediate C-46 Accordingly, intermediate C-46 was prepared in the same way as intermediate C-starting from intermediate C-45 (0.675 g, 1.75 mmol), and tert-butyl 2-iodo-6,7-dihydro-4H-pyrazolo[1,5-alpyrazine-5-carboxylate (CAS [1823835-34-2], 510 mg, 1.46 mmol) affording intermediate C-46 as a white solid, 0.428 g (61%).
Preparation of intermediate C-47 Accordingly, intermediate C-47 was prepared in the same way as intermediate C-starting from intermediate C-46 (428 mg, 0.89 mmol) to afford intermediate C-47 as an orange solid, 0.370 g (99%).
Preparation of intermediate C-48 Accordingly, intermediate C-48 was prepared in the same way as intermediate A-starting from intermediate C-47 (370 mg, 0.89 mmol), to afford intermediate C-48 as a white solid, 0.243 g (53%).
Preparation of intermediate C-49 Accordingly, intermediate C-49 was prepared in the same way as intermediate AE-starting from C-48 (243 mg, 0.47 mmol), yielding 0.190 g (95%) as white solid.
Preparation of compound 82 Accordingly, compound 82 was prepared in the same way as compound 1 starting from intermediate A1-3 (0.73 mmol) and intermediate C-49 (190 mg, 0.46 mmol) yielding 0.189g (72%) as a beige solid.
1H NMR (400 MHz, DMSO) 6 9.21 - 9.11 (m, 1H), 8.56 - 8.43 (m. 2H), 7.89 (t, J
=
8.2 Hz, 1H), 7.28 (d, J = 4.4 Hz, 1H), 7.26 (s, 1H), 6.59 (d, J = 3.9 Hz, 1H), 4.90 (s, 2H), 4.56 (d, J = 5.9 Hz, 2H), 4.30 (t, J = 5.5 Hz, 2H), 4.11 (t, J = 5.4 Hz, 2H), 3.03 (q, J - 7.5 Hz, 2H), 2.34 (s, 3H), 1.29 (t, J - 7.5 Hz, 3H).

2. Characterizing data table Various other compounds that are not specifically described above were also prepared in accordance with the methods described herein (as depicted below) and are also characterised in the table below:
Compound 3 o . "LikrTh o a t Nok...,,N,g,cF3 N
Compound 5 F
0 * N1:1:1 0 C1).......siN --- N+CF3 ii F
Compound 6 F
"L'Isr*Th N = Nol..........N4,C F3 a H
s. \ F
.........._.(..

F

Compounds 9-20 F
N
/ --N

= -Nok/N,V,.0 F3 0 1. / V
01 CI )-N N---N,s,C F3 II

N / N
Compound 9 Compound 10 N . Nosk,,,eNI,CF3 0 ICI, 0 CI
/ \
II
NF * /
I
i 0 \ 0 0 N
H 2 Nr....11/4....
N N
Cl Compound 11 Compound 12 F
N
/ --N / --IseTh = -o-.1,....õ0,C F3 C... .µ...... LII t.....77N * N
,CF3 H 2 NoL.N,V
CI
\

N \ :-....../N
N
Compound 13 Compound F
N.y.Th 0 /--C---e 0 act........FziN N NrrolN,s12,CF3 7.c...zt N N....
N,LI,C F3 o o o N / N
Compound 15 Compound 16 F
0 = /X) 2 0 N...111 FrrtNi N*='' N,sõCF3 = IN:01%...õ..N,42 CF3 i..........N....,s rt S' II H II

N*"...N N'"'AN
Compound 17 Compound 18 o *
10,2,CF3 0 N ¨, /1Th 0 ,II,CF3 ..t... t..tNi N

i CI N
NrS-\..0N i CI...-----:/1 N N
Compound 19 Compound 20 Compound 25-27, 32, 35, 37 o = p--ilr") o 0 N
Nrs-c....õN,g,CF3 No-L.....N

CI
'S' H
--------". N--.....FI lik 0 0 ...s. NN
j \
Compound 25 Compound 26 o l Mk --rr ;1") o o Mk ;4-IrTh o s NN.,cF3 II
s N 0 _____{,, .N\
._....11 , \ 1 N S.-StN
Compound 27 Compound 32 o N.... Ni.tiN . NNa......õ,N 9 CF3 0 sc...\.. z -II

\._\.......N/f 1, /Nr0.1.......,,N H
H
N N--'4"-N
Compound 35 Compound 37 Compounds 38-41, 43, 46 I, INN-2-1,......."'S' S--t,=:-.-N
H II

----C-IttN
Fri II

N N
Compound 38 Compound 39 likN
N..
IN...".) 0 N----"Le=N,..,,,--II likN Nr=:.-L,eN% -NI
ii \
N---4,=N 1µ1.--AN
Compound 40 Compound 41 o le, ;---1 1-N-0 N Mk No.L.....4 'ir ,2........N./ N.....-.L....NcF3 \ o \ o N N N
Compound 43 Compound 46 Compounds 49, 50, 52-54, 57 S...._ t--c.....14No-r 0 o mk, 9-rn rk,,,rTh NCF3 \co\N
II N

Compound 49 Compound 50 * No- N.,N..L)H t lk Nko",,N.nCF3 tIkq¨,:zNi N 0 \
N N
Compound 52 Compound 53 N...N.=Th 0 tN:¨U N-- Nsilo II
N.7 NOL.N...õ-cy 0 H H
\C11:1)1 Compound 54 Compound 57 Compounds 58-62 N N44.-N
ti¨O¨C/ N-eN-11j1 0 0 r.r.1........õN
i; j:t CF3 \sr H

Compound 58 Compound 59 le. Ni > _____________________________________ errTh 0 N...N
.7 N 1 1.....õ..N
o, N \ ,s"
\CN--......Hz .N--"Li NAN NAN
Compound 60 Compound 61 N...eMN
N W N -....-^...:,....., N
N
Compound 62 Compounds 63 and 64 N N...._ N * IN:LN4õ
j_e=N'Th 0 r-NN H ci' ---3 \r`v--.7/
-",..../ N S
N....k....NCF3 II
0,,.....A \ 0 Compound 63 Compound 64 The following compound was also prepared in accordance with the procedures described herein:

1-?Th ' LC-MS
cpd nbr RT %UV MW BPM BPM Method mp 202.3 C (DSC
1 9,4 99,69 567,1 568,1 A Mettler Toledo (5 "C/rnin) 216.0 C (DSC
2 9,7 99,66 568,1 569,1 A Mettler Toledo (5 C/min) 221.6 C (DSC
3 9,4 99,66 585,1 586,1 A 1 Mettler Toledo (5 C/nnin) 229.8 C (DSC
4 9,6 99,37 586,1 587,1 A 1 Mettler Toledo (5 C/nnin) 201.5 C
3,51 97 607 608 B (Mettler Toledo MP50) 243.9 C
6 3,32 99 591,1 592,1 B (Mettler Toledo MP50) LC-MS
cpd nbr RT %UV MW BPM BPM Method mp 243.4 C

97 566,1 567,1 (Mettler 2 Toledo MP50) 234.9 C
3' 30 (Mettler 8 9 99 600,1 601,1 Toledo MP50) 248.3 C
9 '99 599,1 600,1 (Mettler 3 Toledo MP50) 270.0 C
(Mettler 2,82 99 615,1 616 Toledo MP50) 233.4 C
11 2'80 99 615,1 616,1 .. (Mettler 1 Toledo MP50) 273.3 C
(Mettler 12 3,2 97 601,1 602,3 Toledo MPSO) 230.0 C
(Mettler 13 2,64 99 614,1 615 Toledo MP50) 263.4 C
2,65 (Mettler 14 99 600,1 601 Toledo MP50) LC-MS
cpd nbr RT %UV MW BPM BPM Method mp 15 '813 97 586,1 586,9 235.0 C
2' 57 (Metter 16 2 99 616,1 617 Toledo MP50) 263.4 C
(Mettler 17 3,09 99 570,1 571 Toledo MP50) 243.4 C
(Mettler

18 2,78 98 608,1 609,1 Toledo MP50) 238.4 C

19 3'12 99 599,1 600 (Mettler 6 Toledo MP50)

20 '717 95 600,1 601,1 208.3 C
3' 68 (Metter

21 8 98 585 586,1 Toledo (MP50)) 212.15 C

22 2'90 (Metter 99 550,1 552,1 2 Toledo (MP50)) 216.6 C
(Metter

23 3,3 99 561,2 562,2 Toledo MP50) LC-MS
cpd nbr RT %UV MW BPM BPM Method mp 184.9 C

24 2,54 (Metter 99 547,1 548,2 Toledo (MP50)) 236.7 C

25 3'11 (Mettler 99 581,1 582,1 4 Toledo MP50) 198.2 C

26 3'22 96 576,2 577,2 (Mettler Toledo MP50) 174.8 C
(Mettler

27 2,76 95 573,2 574,2 Toledo MP50) 194.9 C
342 (Mettler

28 4 99 574,2 575,2 Toledo MP50) 241.6 C

29 2'71 (Mettler 99 534,1 535,1 6 Toledo MP50) 196.6 C
(Mettler

30 2,71 97 559,2 560,2 Toledo MP50) 164.8 C

31 2'39 99 537,2 538,2 (Metter 7 Toledo (MP50)) 230.0 C
3 06 (Mettler

32 '4 97 539,1 540,1 Toledo MP50) LC-MS
cpd nbr RT %UV MW BPM BPM Method mp 240.0 C

33 272 99 562,2 563,2 (Mettler 2 Toledo MP50) 238.4 C
2' 46 (Metter

34 8 99 533,1 534,1 Toledo (MP50)) 181.5 C

35 2'85 99 575,2 576,2 (Metter 3 Toledo MP50) 214.9 C

36 3'26 99 553,1 554,3 (Metter 1 Toledo (MP50)) 256.7 C

37 1'44 (Mettler 99 416,2 417,2 6 Toledo MP50)

38 '99 559 560,1 (Mettler 8 Toledo MP50) (Mettler

39 3,69 99 573 574,1 Toledo MP50) 240.0 C
1,90 (Mettler

40 99 458,2 459,2 Toledo MP50) LC-MS
cpd nbr RT %UV MW BPM BPM Method mp 216.6 C

41 2'33 95 523,2 524,3 (Mettler Toledo MP50)

42 3'08 (Mettler 99 560,1 561,2 1 Toledo MP50) 245.1 C

43 2'47 99 512,2 513,2 (Mettler 1 Toledo MP50) 235.0 C

44 3'10 99 547,2 548,2 (Mettler 4 Toledo MP50) 246.7 C
2' 78 (Mettler

45 8 99 574,2 575,2 Toledo MP50) 209.9 C
(Mettler

46 1,81 99 457,2 458,2 Toledo MP50 ) 181.5 MCC
2' 549,2 52 (Mettler

47 3 99 Toledo MP50) LC-MS
cpd nbr RT %UV MW BPM BPM Method mp 205.1 C

48 2'32 99 548,2 549,3 (Mettler 4 Toledo MP50) 205.1 C

49 2'32 99 548,2 549,3 (Mettler 4 Toledo MP50) 241.6 C

50 1'55 99 430,2 431,2 (Mettler 2 Toledo MP50) 219.9 C

51 2'16 99 522,2 523,2 (Mettler 7 Toledo MP50) 291.9 C
(Mettler

52 1,37 98 415,2 416,2 Toledo MP50) 228.5 C
2' 26 (Metter

53 3 98 511,2 512,2 Toledo MP50) 116.4 C
1' 83 (Mettler

54 2 99 474,3 475,3 Toledo MP50) LC-MS
cpd nbr RT %UV MW BPM BPM Method mp 198.2 C
SS 1'76 99 473,2 474,3 (Mettler 7 Toledo MP50) 218.3 C
1' 50 (Mettler 56 2 99 429,2 430,2 Toledo MP50) 223.2 C
2$1 (Mettler 57 3 99 554,1 555,1 Toledo MP50) 2' 81 (Mettler 58 5 99 603,2 604,3 Toledo MPS()) 159.8 C
3 19 59 '3 98 631,2 632,4 (Mettler Toledo MP50) 189.9 C
2,30 (Mettler 60 8 97 631,2 632,2 Toledo MP50) 251.7 C

61 2'07 469,2 471,4 (Mettler 2 Toledo MP50) LC-MS
cpd nbr RT %UV MW BPM BPM Method mp 218.2 C
62 1'95 (Mettler 99 468,2 469,2 3 Toledo MP50) 221.6 C
2,36 (Mettler 63 99 539,1 540,3 Toledo MP50) 226.7 C
(Mettler 64 2,64 97 555,1 556,1 Toledo MP50) 193.2 2.14 (Mettler 659 95 552.6 553.2 Toledo MP50) 168.0 66 2'82 97 562.6 563.2 B (Mettler Toledo MP50) 116.2 2 85 (Mettler 67 .3 98 548.5 549.1 Toledo MP50) 164.7 2' 91 (Mettler 68 9 99 574.6 575.1 Toledo MP50) 196.6 2.69 (Mettler 696 97 617.6 618.2 Toledo MP50) 211.5 2.88 (Mettler 70 5 99 632.7 633.2 Toledo MP50) LC-MS
cpd nbr RT %UV MW BPM BPM Method mp 96.2 23 (Mettler 98 562.6 563.2 *1 Toledo MP50) 208.2 2.38 (Mettler 72 5 99 539.5 540.1 Toledo MP50) 2.62 73 99 555.6 556.1 B N/A

153.1 257 (Mettler 747 99 555 5 556.0 Toledo MP50) 229.9 75 2.55 99 555.6 556.1 B (Mettler 1 Toledo MP50) 248.4 2.52 (Mettler 99 556.5 557.1 Toledo MP50) 77 2'86 97 587.9 588.0 B N/A

237.2 2.23 (Mettler 787 99 601.9 602.1 Toledo MP50) 176.4 (Mettler 79 2.25 95 546.6 547.2 Toledo MP50) LC-MS
cpd BPM BPM 1 2 mp nbr RT %UV MW Method 220.0 80 2.87 98 565.5 565.8 B (Mettler 9 Toledo MP50) 218.2 81 2.73 99 546.6 547.1 B (Mettler 9 Toledo MP50) 211.6 82 3.24 99 565.5 566.1 B (Mettler 6 Toledo MP50) 1. Biological Assays/ Pharmacological Examples MIC determination for testing compounds against M. tuberculosis.

Test compounds and reference compounds were dissolved in DMSO and 1111 of solution was spotted per well in 96 well plates at 200x the final concentration. Column 1 and column 12 were left compound-free, and from column 2 to 11 compound concentration was diluted 3-fold. Frozen stocks of Mycobacterium tuberculosis strain (EH4.0 in this case; other strains may be used e.g. H37Rv) expressing green-fluorescent protein (GFP) were previously prepared and titrated. To prepare the inoculum, 1 vial of frozen bacterial stock was thawed to room temperature and diluted to 5x10 exp5 colony forming units per ml in 7H9 broth. 200111 of inoculum, which corresponds to lx10 exp5 colony forming units, were transferred per well to the whole plate, except column 12. 200 1 7H9 broth were transferred to wells of column 12.
Plates were incubated at 37 C in plastic bags to prevent evaporation. After 7 days, fluorescence was measured on a Gemini EM Microplate Reader with 485 excitation and 538 nm emission wavelengths and IC50 and/or pIC5i) values (or the like, e.g. IC5o, IC90, pIC90, etc) were (or may be) calculated.

Appropriate solutions of experimental/test and reference compounds were made in 96 well plates with 7H9 medium. Samples of Mycobacterium tuberculosis strain H37Rv were taken from cultures in logarithmic growth phase. These were first diluted to obtain an optical density of 0.3 at 600 nm wavelength and then diluted 1/100, resulting in an inoculum of approximately 5x10 exp5 colony forming units per ml. 100 1 of inoculum, which corresponds to 5x10 exp4 colony forming units, were transferred per well to the whole plate, except column 12. Plates were incubated at 37 C in plastic bags to prevent evaporation. After 7 days, resazurin was added to all wells. Two days later, fluorescence was measured on a Gemini EM Microplate Reader with 543 excitation and 590 run emission wavelengths and MIC50 and/or pIC50 values (or the like, e.g. 1050, IC90, pIC90, etc) were (or may be) calculated.
TEST 3: Time kill assays Bactericidal or bacteriostatic activity of the compounds can be determined in a time kill kinetic assay using the broth dilution method. In this assay, the starting inoculum of M.
tuberculosis (strain H37Ry and H37Ra) is 106 CFU / ml in Middlebrook (1x) 7H9 broth. The test compounds are tested alone or in combination with another compound (e.g. a compound with a different mode of action, such as with a cytochrome bd inhibitor) at a concentration ranging from 10-301,1M to 0.9-0.31.1M
respectively. Tubes receiving no antibacterial agent constitute the culture growth control. The tubes containing the microorganism and the test compounds are incubated at 37 C.
After 0, 1, 4, 7, 14 and 21 days of incubation samples are removed for determination of viable counts by serial dilution (100 to 106) in Middlebrook 7H9 medium and plating (100 1_11) on Middlebrook 7H11 agar. The plates are incubated at 37 C for 21 days and the number of colonies are determined. Killing curves can be constructed by plotting the logioCFU per ml versus time. A bactericidal effect of a test compound (either alone or in combinaton) is commonly defined as 2-logio decrease (decrease in CFU per ml) compared to Day 0. The potential carryover effect of the drugs is limited by using 0.4% charcoal in the agar plates, and by serial dilutions and counting the colonies at highest dilution possible used for plating.
RESULTS
Compounds of the invention/examples, for example when tested in Test 1 (and/or Test 2) decribed above, may typically have a pIC50 from 3 to 10 (e.g. from 4.0 to 9.0, such as from 5.0 to 8.0) 2. Biological Results Compounds of the examples were tested in Test 1 (and/or in Test 2) described above (in section -Pharmacological Examples-) and the following results were obtained:

Biological data table ple50 cpd nbr 8,11 1 8,00 2 7,21 3 7,90 4 6,64 5 7,08 6 8,07 7 7,58 8 6,44 9 <6.301 10 6,35 11 7,03 12 <6.301 13 6,98 14 6,30 15 6,30 16 6,71 17 6,82 18 6,48 19 6,30 20 7,39 21 7,35 22 7,49 23 8,05 24 6,74 25 6,61 26 6,86 27 7,27 28 7,66 29 7,38 30 7,62 31 pIC50 cpd nbr 7,22 32 7,89 33 7,90 34 <6.301 35 7,79 36 6,34 37 6,55 38 6,91 39 6,30 40 7,34 41 8,30 42 6,55 43 8,66 44 7,82 45 6,55 46 7,70 47 7,59 48 6,30 49 6,77 50 7,38 51 6.68 52 6,92 53 6,88 54 7,30 55 7,13 56 7.58 57 6.91 58 6.96 59 7.03 60 6.41 61 6.76 62 6.72 63 pIC50 cpd nbr 6.88 64 6.48 65 6.57 66 6.79 67 <6.3* 68 7.82 69 7.04 70 <6.3* 71 <6.3 72 <6.3 73 6.51 74 <6.3 75 <6.3 76 6.34 77 <6.3 78 8.17 79 8.06 80 7.69 81 8.55 82 3. Further data on representative compounds of the invention/examples The compounds of the invention/examples may have advantages associated with in vitro potency, kill kinetics (i.e. bactericidal effect) in vitro, PK
properties, food effect, safety/toxicity (including liver toxicity, coagulation, 5-LO oxygenase), metabolic stability, Ames II negativity, MINT negativity, aqueous based solubility (and ability to formulate) and/or cardiovascular effect e.g. on animals (e.g. anesthetized guinea pig).
Data that is generated/calculated may be obtained using standard methods/assays, for instance that are available in the literature or which may be performed by a supplier (e.g. Microsomal Stability Assay ¨ Cyprotex, Mitochondrial toxicity (Glu/Gal) assay ¨
Cyprotex, as well as literature CYP cocktail inhibition assays). GSH can be measured (reactive metabolites, glucuronidation) to observe if a dihydrodiol is observed by LCMS (fragmentation ions), which would correspond to a dihydroxylation on the core heterocycle.

This following data were generated:
Compound 2 LM Clint L/min/mg h/m/r/d = 9.3<7.71<7.71<7.7 MDCK AB+inh: 32.5 MDCK BA/AB: 12.6 PPB h/m % free: 1.17/0.54 Eq sol pH 2/7 ( M): 0.99 am /<0.13 am Fassif/Fessif ( M). <5/24.4 CYPS IC50 uM: all> 20 sync hERG/Na/Ca (IC50 u.M) >30/>10/>10 CTCM: clean up to 10uM
HCS: 32.7 M NC
AMES II: 1 Glu/Gal: >100/>100 Compound 7 LM Clint u.L/min/mg him = 22.6/<7,7 MDCK AB+inh: 21.4 MDCK BA/AB: 61.7 Eq sol pH 2/7 ( M): 125 c/1.62 c sync hERG/Na/Ca (IC50 !LIM) >30/>10/>10 CTCM: clean up to 10uM
CYPS IC50 2C9 15.5; others >20 HCS: >21 uM
Glu/Gal: >200/>200 Compound 79 LM CLint uL/min/mg h/m = 39.8/13.2 Hep t1/2 min h/m = - / 43.3 MDCK AB +inh = 42.7 MDCK BA/AB = --Sol pH 2/4 uM: 574 am/0.062 am Fassif/Fessif uM: 5.6/29.3 CYPS IC50 uM: 2C19 14.4; 2C9 17.7, others > 20 sync hERG/Na/Ca (IC50 uM) 30.2/>10/>10 AMES II: 1 Glu/Gal: >200/>200 Compound 82 LM Clint uL/min/mg h/m =231/28 Hep t1/2 min him = - / 16.5 MDCK AB +inh = 16.2 MDCK AB/BA = --Sol pH 2/4 uM: 12.3 c/<0.02 c Fassif/Fessif uM: 24.5/8.8 CYPS IC50 uM. 2C8 10.6, others > 19.5 sync hERG/Na/Ca (IC 5 0 uM) 20.4/>10/>10 AMES: 1 Glu/Gal: >25/>25 The following further data/results were generated Compound 2 and Compound 7 - were found to have low mitotoxicity (<2 in the Glu/Gal assay) ¨ hence no mitotoxicity alerts Compounds disclosed herein may have the advantage that:
- No in vitro cardiotoxicity is observed (for example either due to the CVS
results or due to the Glu/Gal assay results);
- No reactive metabolite formation is observed (e.g. GSH), for instance as no unwanted reactive metabolites are formed and/or the formation of reactive metabolites was blocked; and/or - There is a relatively higher unbound fraction, for instance as compared to other compounds, for instance prior art compounds.
Certain compounds may also have the additional advantage that they do not form degradants (e.g. that are undesired or may elicit unwanted side-effects).
Compounds, may have the advantage that a faster oral absorption and improved bioavailability are displayed.
Chemical Stability Testing' Compounds disclosed herein may have the advantage that they are chemically more stable than other compounds (e.g. than other kown compounds), for instance as tested in the chemical stability assay described below.

Preliminary Protocol - Add 31.11 of a 10mMDMS0 stock solution to lml of the following solvents in a 1.5m1 HPLC vial.
DMSO (reference solution) H20/Acetonitril 1/1 (assay solution) 0.1N HC1/Acetonitril 1/1 (assay solution) - Mix well, store them on the bench for 72h - Analyse the samples with LCMS
- Compare the chromatograms of the two assay solutions with the reference solution and report the additional peaks as degradation peaks For instance, the following chemical stability results (in % by LCMS) were observed:
Compound 2: conditions ¨ 0.065 mg/mL in SGF with 20% ACN ¨ results ¨ purity =
99.56% (at Ohr), 99.38% (at 0.25hr), 99.21% (at 0.5hr), 98.89%
(at 1hr), 98.28% (at 2hr), 97.1% (at 4hr) (11/2 = 112.81) Compound 6: conditions ¨ 0.052 mg/mL in SGF with 33.3% ACN ¨ results ¨ purity =
99.88 (and remained so, up to 4hrs) Compound 2: DMSO (72hr, rt) = 100%; ACN/0.1N IIC1 (pII
1.6; 72hr, rt) =
90.52%
Compound 10: DMSO (72hr, rt) = 97.03%; ACN/0.1N HC1 (pH 1.6; 72hr, rt) =
100%
Compound 7: DMSO (72hr, rt) = 100%; ACN/0.1N HC1 (pH 1.6;
72hr, rt) =
100%
Compound 14: DMSO (72hr, rt) = 100%; ACN/0.1N HC1 (pH 1.6;
72hr, rt) =
100%
Compound 15: DMSO (72hr, rt) = 97.03%; ACN/0.1N HC1 (pH
1.6; 72hr, rt) 97.49%
Compound 12: DMSO (72hr, rt) = 96.14%; ACN/0.1N HC1 (pH
1.6; 72hr, rt) =
97.06%
Compound 6: ACN/H20 (48hr, rt) = 100%; ACN/0.1N HC1 (pH 1.6; 48hr, rt) 100%
Compound 47: ACN/H20 (48hr, rt) = 99%; ACN/0.1N HC1 (pH
1.6; 48hr, rt) =
100%
Compound 42: ACN/H20 (48hr, rt) = 100%; ACN/0.1N HC1 (pH
1.6; 48hr, rt) =
100%
Compound 66: DMSO (Ohr, rt) = 91%; ACN/H20 (48hr, rt) =
98%; ACN/0.1N
HC1 (pH 1.6; 48hr, rt) = 98%

Compound 24: DMSO (Ohr and 48hr, rt) = 100%; ACN/0.1N HC1 (pH 1.6; Ohr and 48hr, rt) = 100%; ACN/0.1N NaOH (pH 9-10; Ohr and 48hr, rt) = 89.46% and 43.8%
Compound 80: DMSO (Ohr and 48hr_ rt) = 100%; ACN/0.1N HC1 (pH 1.6; Ohr and 48hr, rt) = 100%; ACN/0.1N NaOH (pH 9-10; Ohr and 48hr, rt) = 76.8% and 16.8%
Compound 79: DMSO (Ohr, rt) = 100%; ACN/H20 (48hr, rt) =
100%;
ACN/0.1N HC1 (pH 1.6, 48hr, rt) ¨ 100%
Compound 44: ACN/H20 (48hr, rt) = 100%; ACN/0.1N HC1 (pH
1.6; 48hr, rt) =
100%
Compound 82: ACN/H20 (48hr, rt) = 100%; ACN/0.1N HC1 (pH
1.6; 48hr, rt) =
100%
Compound 81: DMSO (Ohr, rt) = 95%; ACN/1-T20 (48hr, rt) =
100%; ACN/0.1N
HC1 (pH 1.6; 48hr, rt) = 100%
This showed that, under the tested conditions, the compounds were stable, and mostly not susceptible to unwanted degradation in acidic media (or alkaline media, as the case may be).

Claims

-109-

1. A compound of formula (I) wherein A is a 5- or 6-membered ring, which may be aromatic or non-aromatic, and optionally containing 1 or 2 heteroatoms selected from nitrogen and sulfur;
B is a 5-membered heteroaryl group in which at least one of XI, X2 and X3 represents a heteroatom selected from nitrogen sulfur and oxygen;
X' represents =N-, -S-, -0- or =C(R9a)-;
X2 represents =N-, -S-, -0- or =C(R9b)-;
X3 represents =N-, -S-, -0- or =C(R9c)-;
X4 represents =N- or =C(R9d)-;
X5 represents =N- or =C(R9c)-;
le represents one or more (e.g. one, two or three) optional substituents independently selected from selected from halo (e.g. Cl, F), -R4a, -0-R4b, -C(=0)-R4c, -C(=0)-N(R5)(10, -CN and -N(R5a)R5b; or any two RI groups may be taken together (when attached to adjacent atoms of the A ring) to form a 5- or 6-membered ring optionally containing one or two heteroatoms, and which ring is optionally substituted by one or two C1_3 alkyl substituents;
R2 is -C1_4 alkyl optionally substituted by one or more substituents selected from halo and -0C1-3 alkyl;
R3 is H, -R7', -C(=0)-R7b, -S0/-R8 or Hee;
R4a and R4b independently represent hydrogen or -C1-4 alkyl (which, as mentioned herein) may be linear, branched or cyclic alkyl) optionally substituted by one or more substituents selected from halo (e.g. F), -0-CH3 and phenyl;
R4C is -C1_3 alkyl;
R5 and R6 are independently selected from H and -C1_3 alkyl;

Tea and leb independently represent H, 0_6 alkyl or R5a and feb are linked together to form a 3- to 6-membered ring;
R7d represents -0_4 alkyl, optionally substituted by one or more substituents selected from halo, -00_3 alkyl and Het2;
R7b is hydrogen or -C1_3 alkyl (optionally substituted by one or more fluoro atoms);
R8 is Hee, -N(Wc)RSd or -0_4 alkyl optionally substituted by one or more substituents selected from halo (e.g. F) and -0-CH3;
R5c and R" independently represent H, C1-6 alkyl or R5c and R" are linked together to form a 3- to 6-membered ring;
R9d, R9b, R9c, R9d and R9e independently represent H, halo, 0_4 alkyl (itself optionally substituted by one or rnore, e.g. one, substituent(s) selected from fluoro, -CN, -Rwa, _N(Rthc)Rilid and/or _C(0)N(Rlue)Riut, or -0-C14 alkyl (itself optionally substituted by one or more, e.g. one, substituent(s) selected from fluoro, _R10g, -ORmh and/or -N(RIO*101);
R10a, R101), R1Oc, RPM, R10e, RIM, R1Og, R10h, R1O1 and ¨
rc independently represent hydrogen or C1-3 alkyl (optionally substituted by one or more fluoro atoms);
Hetl, Het2 and Het3 independently represent a 5- or 6-membered aromatic ring containing one or two heteroatoms, preferably selected from nitrogen and sulfur, optionally substituted by one or more substitutents selected from halo and 0_3 alkyl (itself optionally substituted by one or more fluoro atoms), or a pharmaceutically-acceptable salt thereof,

2. A compound according to claim 1, wherein:
ring A is represented as follows:

wherein Rla, Rlb and ¨
tc represent according to claim 1 the one or more le optional substituents selected independently.

3. A compound according to claim 1 to 2, wherein ring B is represented as follows:
wherein the right-hand side of (XXII) to (XXIX) is connected to the ring C.

4. A compound according to any one of the preceding claims, wherein ring C is represented as follows:

5.
A compound according to any one of the preceding claims, wherein rings A
and C are as follows:
and integers RI, R2, R3, XI, X2 and X3 are as defined in claim .

6. A compound according to any one of the preceding claims, wherein rings A, B
and C are as follows:
and integers RI, R2 and R3 are as defined in claim 1.

7. A compound as claimed in any one of claims 1 to 6, for use as a pharmaceutical.

8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound as claimed in any one of Claims 1 to 6.

9. A compound as claimed in any one of claims 1 to 6 for use in the treatment of a mycobacterial infection (e.g. tuberculosis).

10. Use of a compound as claimed in any one of claims 1 to 6 for the manufacture of a medicament for the treatment of a mycobacterial infection (e.g.
tuberculosis).

11. A method of treatment of a mycobacterial infection (e.g. tuberculosis), which method comprises administration of a therapeutically effective amount of a compound as claimed in any one of Claim 1 to 6.

12. A combination of (a) a compound as claimed in any one of claims 1 to 6, and (b) one or more other anti-mycobacterial (e.g. anti-tuberculosis) agent.

13. A product containing (a) a compound as claimed in any one of claims 1 to 6, and (b) one or more other anti-mycobacterial (e.g. anti-tuberculosis) agent, as a combined preparation for simultaneous, separate or sequential use in the treatment of a bacterial infection.

14. A process for the preparation of a compound of formula (I) as claimed in Claim 1, which process comprises:
(i) reaction of a compound of formula (XXXXII), in which the integers are defined in Claim 1, with a compound of formula (XXXXIII), wherein the integers are as defined in Claim 1;

(ii) coupling of a compound of formula (XXXXIV), wherein the integers are as defined in Claim 1, and R33 represents a suitable group, e.g.
a suitable leaving group, with a compound of formula (XXXXV), wherein R3 is as defined in Claim 1, and R34 represents a suitable group, e.g.
a suitable leaving group.